November 21 – 23, 2019

Symposium Future of Immunology @ Berlin

Abstract Book

Institute of Anatomy at Wilhelm-Waldeyer-Haus Charité Campus Mitte | Philippstr. 12 | 10115 Berlin Symposium Future of Immunology @ Berlin

Scientific Advisory Board November 21–23, 2019 at Charité – Universitätsmedizin Berlin

Frédéric Geissmann (Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, NY) What is the Symposium all about?

Erika Pearce Immunological research at the highest level has a long tradition at Charité – (Max-Planck-Institute of Immunobiology and Epigenetics, Freiburg) Universitätsmedizin Berlin and represents a major research focus. In the Ton Schumacher coming years, the core departments of immunology are facing a generation (The Netherlands Cancer Institute, Leiden University Medical Center) change at the leadership level, which gives reason to think about strategic and structural amendments to consolidate Charité’s role as a leading institution Eric Vivier in the field of immunology – both in basic and clinical translational research. (Centre d´Immunologie de Marseille-Luminy (CIML), France) With its broad overlap to other research areas, the field of immunology plays a special role requiring interdisciplinary work and inter-organization networ- king. A unique characteristic is the close networking of Charité researchers with their university and non-university partners in Berlin, which enables a Organizing Committee synergistic combination of excellent basic research and clinical research. As of today, immunological research at the Charité is embedded into a network Andreas Diefenbach (Institute of Microbiology, Infectious Diseases and Immunology, Charité) of institutions including the German Rheumatism Research Centre (DRFZ), the Max-Delbrück Center of Molecular Medicine (MDC), the Max-Planck-Institute of Frank Heppner Infection Biology and the Robert-Koch-Institute. We are seeking to make use of (Department of Neuropathology, Charité – Universitätsmedizin Berlin) this excellent research potential and infrastructure even more intensively in the future. Klaus Rajewsky (Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin-Buch) Together with the newly formed Scientific Advisory Board (SAB) consisting of Reinhold E. Schmidt Drs. Erika Pearce (Freiburg, Germany), Eric Vivier (Marseille, France), Ton Schu- (Deutsches Rheuma-Forschungszentrum (DRFZ)) macher (Amsterdam, Netherlands) and Frederic Geissmann (New York, USA), we have the ambitious goal of creating optimal conditions for immunological research at the Charité to be carried out at the highest international level in the future.

To jump-start this process, we welcome you to the symposium ‘Future of Im- munology @ Berlin’ which shall serve as an interactive platform to exchange ideas, concepts and visions how to evolve immunology in Berlin in the next decades. The symposium will take place from November 21 – 23, 2019 in Berlin at the Institute of Anatomy (Wilhelm-Waldeyer-Haus), Charité Campus Mitte, 2 | Philippstr. 12, 10115 Berlin. | 3 Day 1 T H U R S D A Y November 21, 2019 Day 2 F R I D A Y November 22, 2019

11.15 Opening and Welcome by Heyo Kroemer (CEO Charité) 08.45 History of the Institute for Anatomy at Charité by Thomas Jöns (Charité Instiute for Anatomy) Session 1 11.30 - 13.30 | Chair: Ton Schumacher / Eric Vivier 11.30 Ton Schumacher, Amsterdam Session 4 09.00 - 11.00 | Chair: Julia Polansky-Biskup / Hans-Dieter Volk T cell recognition of human cancer 09.00 Hans-Dieter Volk, Berlin 12.00 Burkhard Becher, Zurich Translational immunology – from pathogenesis to new diagnostics and therapies Mapping the Immune System in chronic inflammatory diseases: one cell at a time Julia Polansky-Biskup, Berlin 12.30 Bodo Grimbacher, Freiburg Utilizing epigenetics for the benefit of Advanced Therapies What can rare immuno­deficiencies teach us in immunology? 09.30 Hedda Wardemann, Heidelberg 13.00 Gerhard Krönke, Erlangen Qualitative assessments of adaptive immune responses at single-cell level The road from autoimmunity to inflammation 10.00 Alexander Scheffold, Kiel 13.30 L U N C H (Foyer) Antigen-specific regulation of tolerance & inflammation in humans Session 2 14.30 - 16.30 | Chair: Gerd-Rüdiger Burmester / Antigoni Triantafyllopoulou 10.30 Simon Fillatreau, Paris Novel insights into the roles of the adaptive immune system in immune regulati- 14.30 Gerd-Rüdiger Burmester, Berlin on and immune-mediated inflammatory diseases Charité and the DRFZ - A unique model of tight interaction between clinical and translational science 11.00 C O F F E E B R E A K Antigoni Triantafyllopoulou, Berlin Session 5 11.30 - 13.30 | Chair: Frederic Geissmann / Eric Vivier Innate immunity at the crossroad of autoimmunity and organ damage 11.30 Eric Vivier, Marseille 15.00 Axel Kallies, Melbourne Harnessing innate immunity in cancer therapy Effector differentiation of regulatory and cytotoxic T cells 12.00 Martin Kriegel, New Haven 15.30 Gioacchino Natoli, Milan Suppression of translocating pathobionts in autoimmunity – an interventional Accessibility and usage of the genomic regulatory information in immune responses paradigm for the future of immunology 16.00 Tal Arnon 12.30 Manolis Pasparakis, Köln Perivascular pathways direct one-way migration of T cells into splenic T zones The intimate connection between cell death and inflammation 16.30 C O F F E E B R E A K (Foyer) 13.00 Katja Simon, Oxford Session 3 17.00 - 19.00 | Chair: Andreas Radbruch / Chiara Romagnani Autophagy and Proteostasis in Immune Senescence 17.00 Andreas Radbruch, Berlin | Cellular pathology of chronic inflammatory diseases 13.30 L U N C H (Foyer) Chiara Romagnani, Berlin | Innate immune checkpoints of inflammation 14.30 ROUND TABLE – Panel Discussion | Chair: Andreas Diefenbach / Jens Steinbrink Michela Di Virgilio, Frederic Geissmann, Andreas Radbruch, Klaus Rajewsky, 17.30 Georg Schett, Erlangen Chiara Romagnani, Ton Schumacher, Eric Vivier Towards a molecular profiling of inflammatory disease The Future of Immunology 18.00 Dietmar Zehn, München 15.30 C O F F E E B R E A K (Foyer) InTOXication causes T-cell exhaustion in chronic infection 18.30 Claudia Waskow, Jena Generation and Regeneration of Hematopoietic Stem Cells 4 | 20.00 open end > Dinner with Students | 5 Day 2 F R I D A Y November 22, 2019 Day 3 S A T U R D A Y November 23, 2019

Session 6 16.00 - 18.00 | Chair: Thomas Blankenstein / Gerald Willimsky Session 7 09.00 - 11.00 | Chair: Leif-Erik Sander / Norbert Suttorp 16.00 Thomas Blankenstein, Berlin and Gerald Willimsky, Berlin 09.00 Norbert Suttorp, Berlin and Leif-Erik Sander, Berlin T-Immunology Host-directed approaches to diagnostics, treatment, and prevention of 16.30 Andrea Schietinger, New York infectious diseases Molecular and epigenetic programs defining tumor-specific T cell differentiation 09.30 Susanne Herold, Gießen 17.00 Mathias Heikenwälder, Heidelberg Macrophages – key effector cells in organ damage and injury resolution On the role of immune cells on NASH/liver cancer and its consequences for in the infected lung therapy 10.00 Florian Klein, Köln 17.30 Florian Greten, Frankfurt a.M. Broadly Neutralizing Antibodies for HIV-1 Immunotherapy The inflammatory tumor microenvironment 10.30 Melanie Greter, Zurich 19.00 open end > Dinner at Charité Hörsaalruine Life and Fate of Brain Macrophages 11.00 C O F F E E B R E A K Session 8 11.30 - 13.30 | Chair: Frederic Geissmann / Ton Schumacher 11.30 Frederic Geissmann, New York Genetic and developmental basis for macrophages functions 12.00 Thomas Gebhardt, Melbourne A new melanoma platform to study spontaneous immunity, cancer-immune equilibrium and immune control of metastatic disease 12.30 Michael Dustin, Oxford Supramolecular attack particles: a new cytotoxic biomaterial 13.00 L U N C H and end of symposium

6 | | 7 Ton Schumacher Session 1 “T cell recognition of human cancer”

The Netherlands Cancer Institute 5 SELECTED PUBLICATIONS Leiden University Medical Center The Netherlands 1. Blank CU, Rozeman EA, Fanchi LF, Sikorska K, van de Wiel B, Kvistborg P, Krijgsman O, van den Barber M, Broeks A, van Thienen JV, Mallo HA, Adriaansz S, ter Meulen S, Pronk LM, Grijpink-Ongering L, Bruning A, Gittelman R, Warren S, van Tinteren H, Peeper D, Haanen JB, van Akkooi AC, Schumacher BIOSKETCH TN. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage 3 melanoma. Nat Med. 2018 https://doi.org/10.1038/s41591-018-0198-0. Ton N. Schumacher is Principal Investigator at The Netherlands Cancer Institute and Professor of Im- munotechnology at Leiden University, where his research focuses on the dissection and manipulation 2. Mezzadra R, Sun C, Jae LT, Gomez-Eerland R, de Vries E, Wu W, Logtenberg MEW, Slagter M, Rozeman of T cell recognition of human cancer. Schumacher is recipient of, amongst others, the Amsterdam EA, Hofl and I, Broeks A, Horlings HM, Wessels LFA, Blank CU, Xiao Y, Heck AJR, Borst J, Brummelkamp Inventor Award, Queen Wilhelmina Research Award, Meyenburg Award, and W.B. Coley Award. Next to TR, Schumacher TNM. Identifi cation of CMTM6 and CMTM4 as PD-L1 protein regulators.Nature . 2017 his academic role, Schumacher is founder of 4 biotechs and venture partner at Third Rock Ventures. Sep 7;549(7670):106-110. doi: 10.1038/nature23669. Epub 2017 Aug 16. PubMed PMID: 28813410.

3. Strønen E, Toebes M, Kelderman S, van Buuren MM, Yang W, van Rooij N, Donia M, Böschen ML, ABSTRACT Lund-Johansen F, Olweus J, Schumacher TN. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science. 2016 Jun 10;352(6291):1337-41. doi: 10.1126/science.aaf2288. Epub Inhibitors of the immune checkpoint PD-1 show impressive clinical activity in a subset of patients across 2016 May 19. PubMed PMID: 27198675. a range of tumor types. However, little is known on the immunological response that human cancers display upon such PD-1 blockade, and which baseline properties in the tumor microenvironment (TME) 4. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015 Apr can be used to predict immune re-activation by therapy. To address this question, we developed a 3;348(6230):69-74. doi: 10.1126/science.aaa4971. Review. PubMed PMID: 25838375. human tumor explant platform that preserves the TME but allows for perturbation by immunothera- peutics. Using this platform, we have analyzed the immunological response of a cohort of 37 tumors 5. Linnemann C, van Buuren MM, Bies L, Verdegaal EM, Schotte R, Calis JJ, Behjati S, Velds A, Hilk- from fi ve cancer types (melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, renal cell mann H, Atmioui DE, Visser M, Stratton MR, Haanen JB, Spits H, van der Burg SH, Schumacher TN. carcinoma) to ex vivo PD-1 blockade. Data obtained reveal that immune activation by PD-1 blockade High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells is restricted to approximately 35% of tumors and that such immunological responses correlate with in human melanoma. Nat Med. 2015 Jan;21(1):81-5. doi: 10.1038/nm.3773. Epub 2014 Dec 22. PubMed clinical anti-PD-1 response. Furthermore, a number of baseline parameters were defi ned that predict PMID: 25531942. the capacity for immune re-activation by PD-1 blockade. The diversity in the immunological response of human cancers to PD-1 blockade described here, and the identifi cation of correlates of immune re-acti- vation helps explain the divergent response that has been observed clinically.

NOTES

8 | | 9 Burkhard Becher Session 1 “Mapping the Immune System in chronic inflammatory diseases: one cell at a time”

Institute of Experimental Immunology-Experimental Research 5 SELECTED PUBLICATIONS University of Zurich, Switzerland 1. Galli E, Hartmann FJ, Schreiner B, Ingelfinger F, Arvaniti E, Diebold M, Mrdjen D, van der Meer, F, Krieg C, Al Nimer F, Sanderson N, Stadelmann C, Khademi M, Piehl F, Claassen M, Derfuss T, Olsson T and Becher B. GM-CSF and CXCR4 Define a T Helper Cell Signature in Multiple Sclerosis,Nat Med. BIOSKETCH 2019;25(8):1290-300

Burkhard Becher is an immunologist specialized in inflammation research and Director of the Institu- 2. Komuczki J, Tuzlak S, Friebel E, Hartwig T, Spath S, Rosenstiel P, Waisman A, Opitz L, Oukka M, te of experimental Immunology at the University of Zurich in Switzerland. He studied Biology at the Schreiner B, Pelczar P and Becher B. Fate-Mapping of GM-CSF Expression Identifies a Discrete Sub- University of Cologne in Germany and specialized in Molecular Genetics and Biochemistry. In 1995, for set of Inflammation-Driving T Helper Cells Regulated by Cytokines IL-23 and IL-1beta.Immunity . his graduate studies he went to study at McGill University in Canada to train in Neuroimmunology with 2019;50(5):1289-304. Jack Antel. His work focused on the role of microglia cells as brain-resident myeloid cells capable of instructing self-reactive T cells in the context of autoimmune neuro-inflammation. In 1999 he joined the 3. Krieg C, Nowicka M, Guglietta S, Schindler S, Hartmann FJ, Weber LM, Dummer R, Robinson MD, lab of Randy Noelle at the Dartmouth Medical School to extend his work to in vivo models of chronic Levesque MP and Becher B. High-dimensional single-cell analysis predicts response to anti-PD-1 inflammatory diseases and transplantation immunology using innovative transgenic mouse tools. He immunotherapy. Nat Med. 2018;24(2):144-53. developed tools to specifically manipulate tissue-resident phagocytes in vivo during inflammation. Burkhard’s focus is the function of cytokines and how these molecules permit cell-cell communication 4. Spath S, Komuczki J, Hermann M, Pelczar P, Mair F, Schreiner B and Becher B. Dysregulation of the between immune cells. In 2003, he was recruited as Assistant Professor to the University Hospital of Cytokine GM-CSF Induces Spontaneous Phagocyte Invasion and Immunopathology in the Central Zurich. There he continued to define the cytokine networks in inflammation. In 2008, he became full Nervous System. Immunity. 2017;46(2):245-60. professor and chairman at the Institute of Experimental Immunology at the University of Zurich and heads the Unit for Inflammation Research. 5. Becher B, Schlitzer A, Chen J, Mair F, Sumatoh HR, Teng KW, Low D, Ruedl C, Riccardi-Castagnoli P, Poidinger M, Greter M, Ginhoux F and Newell EW. High-dimensional analysis of the murine myeloid cell system. Nat Immunol. 2014;15 ABSTRACT

Chronic inflammatory diseases are mediated by dysregulated immune homeostasis. However, there are still great gaps in our knowledge of inflammatory cascades, in particular in patients who suffer from chronic inflammation. Such knowledge may help to identify biomarkers aiding the diagnosis of the mo- nitoring of disease activity and the identification of therapeutic targets to stop chronic inflammation. One reason for the lack of solid biomarkers is the hypothesis-driven nature of investigations, which bias the investigation toward arbitrarily classified cell subsets and biomarkers. The increasing number of parameters which can be measured simultaneously allow for the concomitant characterization of NOTES phenotypic and functional properties at the single cell level and led to major discoveries including new cell types, stratifying biomarkers and disease-relevant signatures. The emergence of cytometers capable of measuring more than 100 parameters simultaneously and in large cohort of patients, brings about a new area of biomarker discovery, where intelligent algorithms and computer-aided analysis allow for a thus far unprecedented view onto the single cell proteome. I will discuss recent advances in single cell technologies and how we apply this technology to immunophenotype patients with inflam- matory disease for the identification of disease-relevant signatures for diagnosis, patient stratification and therapy responses.

10 | | 11 Bodo Grimbacher Session 1 “What can rare immunodefi ciencies teach us in immunology?”

Scientifi c Director, 5 SELECTED PUBLICATIONS Center for Chronic Immunodefi ciency, University Medical Center Freiburg 1. Rauer S, Marks R, Urbach H, Warnatz K, Nath A, Holland S, Weiller C, Grimbacher B. Treatment of Progressive Multifocal Leukoencephalopathy with Pembrolizumab. N Engl J Med. 2019. (letter) Apr 25;380(17):1676-1677. BIOSKETCH 2. Frey-Jakobs S, Hartberger JM, Fliegauf M, Bossen C, Wehmeyer ML, Neubauer JC, Bulashevska A, Academic training Proietti M, Fröbel P, Nöltner C, Yang L, Rojas-Restrepo J, Langer N, Winzer S, Engelhardt KR, Glocker • 1988 – 1995 Medical studies in Aachen, Freiburg and Hamburg C, Pfeifer D, Klein A, Schäffer AA, Lagovsky I, Lachover-Roth I, Béziat V, Puel A, Casanova JL, Flecken- stein B, Weidinger S, Kilic SS, Garty BZ, Etzioni A, Grimbacher B. ZNF341 controls STAT3 expression Scientifi c qualifi cations and thereby immunocompetence. Sci Immunol. 2018. 15;3(24). • 2006 Habilitation in Internal Medicine, University of Freiburg (Mentor: Prof. H. H. Peter) • 1995 Dissertation in Medicine, University of Freiburg (Supervisor: Prof. H. Eibel) 3. Fliegauf M, Bryant VL, Frede N, Slade C, Woon ST, Lehnert K, Winzer S, Bulashevska A, Scerri T, Leung E, Jordan A, Keller B, de Vries E, Cao H, Yang F, Schäffer AA, Warnatz K, Browett P, Douglass J, Amera- Postgraduate Positions tunga RV, van der Meer JW, Grimbacher B. Haploinsuffi ciency of the NF-κB1 Subunit p50 in Common • since 2011 Scientifi c Director and consultant at the CCI, Medical Center - University of Freiburg Variable Immunodefi ciency.Am J Hum Genet. 2015. 97(3):389-403. • 2006 - 2011 Consultant and Head of Marie-Curie Research Group, Dept. of Immunology, Royal Free Hospital & University College London, UK 4. Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, Bulashevska A, Petersen BS, Schäffer • 2000 - 2006 Assistant lecturer and Emmy Noether-Fellow of the DFG, Division of Rheumatology AA, Grüning BA, Unger S, Frede N, Baumann U, Witte T, Schmidt RE, Dueckers G, Niehues T, Sene- and Clinical Immunology, Medical Center – University of Freiburg viratne S, Kanariou M, Speckmann C, Ehl S, Rensing-Ehl A, Warnatz K, Rakhmanov M, Thimme R, • 1997 - 2000 Postdoctorate, NIH, National Human Genome Institute, Bethesda, MD, USA Hasselblatt P, Emmerich F, Cathomen T, Backofen R, Fisch P, Seidl M, May A, Schmitt-Graeff A, Ikemizu • 1995 – 1997 Postdoctorate, Division of Rheumatology and Clinical Immunology, S, Salzer U, Franke A, Sakaguchi S, Walker LS*, Sansom DM*, Grimbacher B*. Autosomal dominant Medical Center - University of Freiburg immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014. 20(12):1410-6.

5. Glocker, E. O., D. Kotlarz, K. Boztug, E. M. Gertz, A. A. Schaffer, F. Noyan, M. Perro, J. Diestelhorst, A. ABSTRACT Allroth, D. Murugan, N. Hatscher, D. Pfeifer, K. W. Sykora, M. Sauer, H. Kreipe, M. Lacher, R. Nustede, C. Woellner, U. Baumann, U. Salzer, S. Koletzko, N. Shah, A. W. Segal, A. Sauerbrey, S. Buderus, S. B. Primary immune defi ciencies are „an experiment of nature“ (Robert Good). The severity of the immune Snapper, B. Grimbacher, and C. Klein. Infl ammatory bowel disease and mutations affecting the defect in patients is variable, hence, the fi tness of the immune system in humans rather represents a interleukin-10 receptor. N Engl J Med. 2009. 361: 2033-2045. bell-shaped curve with very few individuals suffering from severe immune defi ciencies, and many more suffering from milder forms of immune incompetence. The work of Prof. Grimbacher hypothesizes that the genetic make-up of each individual has a major NOTES impact on the fi tness of the immune system. He therefore searches for genetic variants explaining immune dysregulation. His group was successful in the identifi cation of several monogenetic defects in disorders such as congenital neutropenia, chronic mucocutaneous candidiasis, infl ammatory bowel disease, the hyper-IgE syndrome, and several forms of antibody defi ciencies. Prof. Grimbacher will demonstrate how patients with primary immune defi ciencies teach us about the biology of the human immune system. He will give examples including Candida control, infl ammatory bowel disease, and antibody production. He will give examples of how primary immune defi ciencies aided in the identifi cation of specifi c “Achilles heels” in the immune system, which are now being targe- ted in more prevalent diseases such as B cell lymphomas, and in future possibly also in autoimmune- or 12 | atopic conditions, or in multiple myeloma. | 13 Gerhard Krönke Session 1 “The road from autoimmunity to inflammation”

Translational Immunology, 5 SELECTED PUBLICATIONS Medicine 3, University Clinic Erlangen 1. Culemann S, Grüneboom A, Nicolás-Ávila JÁ, Weidner D, Lämmle KF, Rothe T, Quintana JA, Kirchner P, Krljanac B, Eberhardt M, Ferrazzi F, Kretzschmar E, Schicht M, Fischer K, Gelse K, Faas M, Pfeifle R, Ackermann JA, Pachowsky M, Renner N, Simon D, Haseloff RF, Ekici AB, Bäu- BIOSKETCH erle T, Blasig IE, Vera J, Voehringer D, Kleyer A, Paulsen F, Schett G, Hidalgo A and Krönke G. Locally renewing resident synovial macrophages provide a protective barrier for the joint. After graduating from the Medical University of Vienna in 2002, Gerhard Krönke worked as postdoctoral Nature. 2019 Aug 7. In press researcher at the Medical University of Vienna (2002-2004) and the University of Virginia, Charlottesvil- le (2004-2006). From 2006-2015 he conducted his clinical training in Internal Medicine and subsequently 2. Pfeifle R, Rothe R, Ipseiz N, Scherer HU, Culemann S, Harre U, Ackermann JA, Seefried M, Kleyer in Rheumatology at the University Hospital Erlangen, where he is currently working as Senior Physician A, Uderhardt S, Haugg B, Hueber AJ, Daum P, Heidkamp GF, Ge C, Böhm S, Lux A, Schuh W, Ma- at the Department of Internal Medicine 3 since 2012. In 2016, he was appointed Professor of Translati- gorivska I, Nandakumar KS, Lönnblom E, Becker C, Dudziak D, Wuhrer M, Rombouts Y Koeleman onal Immunology at the University of Erlangen-Nürnberg. His research focuses on cellular, molecular CA, Toes R, Winkler TH, Holmdahl R, Herrmann M, Blüml S, Nimmerjahn F, Schett G and Krönke G. and metabolic pathways involved in the maintenance and break of immunological self-tolerance as well Regulation of autoantibody activity by the IL-23/Th17 axis promotes the onset of autoimmune disease. as the onset and resolution of inflammation. In particular, he is trying to understand the mechanisms Nat Immunol. 2017 Jan;18(1):104-113 and events leading to the development of inflammatory autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematodes and to develop novel strategies for their diagnosis and 3. Rothe T, Gruber F, Uderhardt S, Ipseiz N, Rössner S, Oskolkova O, Blüml S, Leitinger N, Bi- treatment. In 2014 he received an ERC Starting grant and is currently acting as the spokesperson of the cker W, Bochkov VN, Yamamoto M, Steinkasserer A, Schett G, Zinser E and Krönke G. 12/15-li- DFG research unit FOR2886 “PANDORA” (Pathways triggering AutoimmuNity and Defining Onset of early poxygenase-mediated enzymatic lipid oxidation regulates DC maturation and function. Rheumatoid Arthritis). J Clin Invest. 2015 May 1;125(5):1944-1954

4. Scholtysek C, Katzenbeisser J, Fu H, Uderhardt S, Ipseiz N, Stoll C, Zaiss MM, Stock M, Böhm C, Kleyer ABSTRACT A, Hess A, Engelke K, David JP, Djouad F, Tuckermann JP, Desvergne B, Schett G and Krönke G. PPARβ/δ governs Wnt signaling and bone turnover. Nat Med. 2013 2013 May;19(5):608-13 Chronic inflammatory and autoimmune diseases are prevalent disorders that represent a major burden for patients and society. The reasons for a failure in immune tolerance and onset of inflammation in 5. Uderhardt S, Herrmann M, Oskolkova O, Aschermann S, Bicker W, Ipseiz N, Sarter K, Frey such individuals remain incompletely understood. During the last years, we have sought to unravel B, Rothe T, Voll R, Nimmerjahn F, Bochkov VN, Schett G and Krönke G. 12/15-Lipoxygena- underlying mechanistic and molecular aspects such as the contribution of myeloid cells to the main- se Orchestrates the Clearance of Apoptotic Cells and Maintains Immunologic Tolerance. tenance of tissue homeostasis, self-tolerance and autoimmunity-induced inflammation as well as the Immunity. 2012 May 25;36(5):834-46. exact role of T and B cells during the pathogenesis of inflammatory autoimmune diseases such as rheumatoid arthritis (RA). These insights do not only help to understand basic aspects of innate and adaptive immunity during health and disease, but might additionally aid the development of novel di- NOTES agnostic and therapeutic approaches in the near future. Examples include the current development of metabolic MRI techniques that aim to decipher the molecular patterns of musculoskeletal inflammation in a non-invasive manner as well as a clinical trial that seeks to re-induce immune tolerance in patients suffering from RA by sequentially targeting B and T cells.

14 | | 15 Gerd-Rüdiger Burmester Session 2 “Charité and the DRFZ - A unique model of tight interaction between clinical and translational science”

Director, 5 SELECTED PUBLICATIONS Department of Rheumatology and Clinical Immunology Charité - University Medicine Berlin 1. Burmester GR, Kremer JM, Van den Bosch F, Kivitz A, Bessette L, Li Y, Zhou Y, Othman AA, Pangan AL, Camp HS. Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a ran- BIOSKETCH domised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018 391:2503-2512.

Gerd-R. Burmester, MD, is Professor of Medicine and Director in the Department of Rheumatology and 2. Ospelt C, Bang H, Feist E, Camici G, Keller S, Detert J, Krämer A, Gay S, Ghannam K, Burmester GR. Clinical Immunology at the Charité University Hospital, Free University and Humboldt University of Carbamylation of vimentin is inducible by smoking and represents an independent autoantigen in Berlin. He earned his medical degree from Hannover Medical School and completed a residency at the rheumatoid arthritis. Ann Rheum Dis. 2017 76:1176-1183. Medical School of the University of Erlangen-Nuremberg. He was awarded a postdoctoral fellowship at Rockefeller University in New York, and was a visiting scholar at the Hospital for Joint Diseases, Mount 3. Burmester GR, Blanco R, Charles-Schoeman C, Wollenhaupt J, Zerbini C, Benda B, Gruben D, Wallen- Sinai School of Medicine, New York. He served as President of the German Society of Rheumatology stein G, Krishnaswami S, Zwillich SH, Koncz T, Soma K, Bradley J, Mebus C; ORAL Step investigators. from 2001-2002 and was President of EULAR (European League Against Rheumatism) from 2015 – 2017. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arth- Since 2017, he is President of the Board of Trustees, FOREUM Foundation for Research in Rheumatology. ritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. His awards include the Jan van Breemen Medal of the Dutch Society of Rheumatology, the Carol-Nach- Lancet. 2013 381(9865):451-60. man Price, and he was chosen as Master of the American College of Rheumatology in 2019. 4. Detert J, Bastian H, Listing J, Weiß A, Wassenberg S, Liebhaber A, Rockwitz K, Alten R, Krüger K, As partner of the DRFZ, his clinical interests focus on inflammatory joint diseases and systemic autoim- Rau R, Simon C, Gremmelsbacher E, Braun T, Marsmann B, Höhne-Zimmer V, Egerer K, Buttgereit mune disorders, where he was involved in the major new therapeutic approaches including biologics, F, Burmester GR. Induction therapy with adalimumab plus methotrexate for 24 weeks followed by autologous stem cell transplantation and JAK-inhibitors. Translational research includes the role of methotrexate monotherapy up to week 48 versus methotrexate therapy alone for DMARD-naive immune response genes in rheumatic diseases, the delineation of immune cells in tissue sites of in- patients with early rheumatoid arthritis: HIT HARD, an investigator-initiated study. Ann Rheum Dis. flammation and the analysis of biomarkers in rheumatology. 2013 72:844-50.

5. Alexander T, Thiel A, Rosen O, Massenkeil G, Sattler A, Kohler S, Mei H, Radtke H, Gromnica-Ihle E, ABSTRACT Burmester GR, Arnold R, Radbruch A, Hiepe F. Depletion of autoreactive immunologic memory follo- wed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces Rheumatic and musculoskeletal diseases (RMDs), including systemic autoimmune diseases, lead to a long-term remission through de novo generation of a juvenile and tolerant immune system. Blood. great burden both for the affected patients and for the society as a whole with premature disability, 2009 113(1):214-23. loss of working hours and - if uncontrolled - a lower life expectancy. They are also one of the three main reasons why a patient visits a family doctor or specialist. The Department of Rheumatology and Clinical Immunology of the Charité and the German Rheumatology Research Center (DRFZ) tightly work NOTES together to meet the challenges of optimal disease recognition including modern epidemiology as well as novel diagnostic and therapeutic approaches. There is a close cooperation between epidemiologists, natural scientists and physicians from all areas of rheumatology research. We recognize that, despite major advances, there is still a great need to develop new treatment modalities. Our ultimate goal will be the cure of RMDs, and where this is not possible, a sustained remission without damage and pain. These approaches started and are ongoing in the areas of re-directing or modulating the immune sys- tem with biologic treatment strategies, an “Immune Reset“ with autologous stem cell transplantation, targeting long lived plasma cells using CD38 and the proteasome system as well as IL-2 treatment to generate T regulatory cells in vivo. 16 | | 17 Antigoni Triantafyllopoulou Session 2 “Innate immunity at the crossroad of autoimmunity and organ damage”

Department of Rheumatology and Clinical Immunology, 5 SELECTED PUBLICATIONS Charité University Hospital and German Rheumatism Research Centre, a Leibniz Institute, Berlin 1. Gronke, K, P.P.Hernández PP, Zimmermann J, Klose C.S.N., Kofoed-Branzk M, Guendel-Rojas F, Wit- kowski M, Tizian C, Amann L, Schumacher F, Glatt H, Triantafyllopoulou A, and Diefenbach A. 2019. Interleukin-22 protects intestinal epithelial stem cells against genotoxic stress. Nature 566 (7743): BIOSKETCH 249-253.

Antigoni Triantafyllopoulou, M.D./Ph.D., is a Rheumatologist in the Department of Rheumatology and 2. Viau A, Bienaimé F, Lukas K, Todkar AP, Knoll M, Yakulov TA, Hofherr A, Kretz O, Helmstädter M, Clinical Immunology at the Charité University Hospital and a Liaison Group Leader at the German Rheu- Reichardt W, Braeg S, Aschman T, Merkle A, Pfeifer D, Dumit VI,Gubler MC, Nitschke R, Huber TB, Terzi matism Research Centre, Berlin. She earned her medical degree and doctoral title from the National F, Dengjel J, Grahammer F, Köttgen M, Busch H, Boerries M, Walz G, Triantafyllopoulou A, Kuehn University of Athens Medical School. She then completed a residency in Internal Medicine at the Mon- EW. 2018. Cilia-localized LKB1 regulates chemokine signaling, macrophage recruitment, and tissue tefiore Medical Centre, Albert Einstein College of Medicine and a fellowship in Rheumatology at the homeostasis in the kidney. EMBO J. 37 (15): e98615. Hospital for Special Surgery, Weill Medical College of Cornell University, New York, where she showed that macrophages and type I interferons induce severe lupus nephritis (PNAS 2010). In 2009 she joined 3. Horn V, Triantafyllopoulou A. 2018. DNA damage signaling and polyploid macrophages in chronic the Center of Chronic Immunodeficiency and the Department of Rheumatology in Freiburg University inflammation.Curr Opin Immunol. 50: 55-63. Medical Center. Her group found that DNA damage signaling induced by persistent inflammatory stimuli promotes the formation of polyploid granuloma macrophages with tissue remodelling signatures (Cell 4. Herrtwich L, Nanda I, Evangelou K, Nikolova T, Horn V, Sagar, Erny D, Stefanowski J, Rogell L, Klein C, 2016). For her work in granuloma macrophages she has been awarded a European Union Marie Curie Gharun K, Follo M, Seidl M, Kremer B, Münke N, Senges J, Fliegauf M, Aschman T, Pfeifer D, Sarrazin S, International Reintegration Grant (2011-2014) and recently an ERC Starting Grant (DDRMac, 2018). In Sieweke M, Wagner D, Dierks C, Haaf T, Ness T, Zaiss MM, Voll RE, Deshmukh SD, Prinz M, Goldmann T, 2017, Antigoni moved to Berlin where she built up a group on Innate Immunity in Rheumatic Diseases. Hölscher C, Hauser AE, Lopez-Contreras AJ, Grün D, Gorgoulis V, Diefenbach A, Henneke P, and Trian- Besides basic research, she runs an outpatient clinic for SLE patients tafyllopoulou A. 2016. DNA damage signaling instructs polyploid macrophage fate in granulomas. Cell 167: 1264-1280.

ABSTRACT 5. Triantafyllopoulou A, Franzke C-W, Seshan SV, Perino G, Girardi G, Kalliolias G, Ramanujam M, van Rooijen N, Davidson A, and LB Ivashkiv. 2010. Proliferative lesions and metalloproteinase activity in Autoimmunity may be necessary but is often not sufficient for organ damage. The conditions under murine lupus nephritis mediated by type I interferons and macrophages. Proc Natl Acad Sci U S A which organ damage occurs remain largely unknown and are key to successful treatment approaches. 107:3012-3017. To explore these conditions, we have interrogated the significance, function and crosstalk of innate immune cells in an animal model of systemic lupus erythematosus, a prototypic autoimmune disease. Our data support that innate immunity critically amplifies autoantibody mediated tissue damage in a pathway independent of systemic loss of tolerance. These findings deepen the gap between loss of tolerance and tissue damage and reveal nodes in disease pathogenesis that can serve as treatment NOTES targets.

18 | | 19 Axel Kallies Session 2 “Effector differentiation of regulatory and cytotoxic T cells”

Professor, Molecular Immunology Laboratory, The Peter Doherty Institute 5 SELECTED PUBLICATIONS for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne 1. Cretney E, Xin A, Shi W, Minnich M, Masson F, Miasari M, Belz G, Smyth GK, Busslinger M, Nutt SL, Kallies A 2011. The transcription factors Blimp1 and IRF4 jointly control differentiation and function • Honorary Principal Fellow, The Walter and Eliza Hall Institute of Medical Research of effector regulatory T cells. Nature Immunology 12, 304-11 (376 cites). • Research Fellow of the National Health and Medical Research Council (NHMRC) of Australia 2. Man K, Miasari M, Shi W, Xin A, Henstridge DC, Preston S, Pellegrini M, Belz GT, Smyth GK, Febbraio MA, Nutt SL, Kallies A 2013. The transcription factor IRF4 is essential for TCR affinity-mediated me- BIOSKETCH tabolic programming and clonal expansion of T cells. Nature Immunology 14, 1155-65 (205 cites).

Axel Kallies completed his PhD in Berlin, Germany, working on the role of transcription factor IRF8 in 3. Vasanthakumar A, Moro K, Xin A, Liao Y, Gloury R, Kawamoto S, Fagarasan S, Mielke LA, Afshar-Sterle the development of macrophages. He then started his postdoctoral fellowship in the group of Stephen S, Masters SL, Nakae S, Saito H, Wentworth JM, Li P, Liao W, Leonard WJ, Smyth GK, Shi W, Nutt SL, Nutt at the Walter and Eliza Hall Institute (WEHI), Melbourne, Australia, where he worked on the control Koyasu S, Kallies A. 2015 The transcriptional regulators IRF4, BATF and IL-33 orchestrate develop- of plasma cell differentiation and established the central role of Blimp1 in this process. In 2010 he ment and maintenance of adipose tissue-resident regulatory T cells. Nature Immunology 16, 276- started his laboratory at the WEHI and began his research focused on T-cell biology. During this time, 285 (249 cites). his lab focussed on transcriptional regulators in the differentiation of conventional and regulatory T cells. In 2017, he was recruited to the University of Melbourne. His team studies the molecular cont- 4. Mackay LK, Minnich M, Kragten NAM, Liao Y, Nota B, Seillet C, Zaid A, Man K, Preston S, Freestone D, rol of lymphocyte differentiation in response to antigen with a particular focus on T cells residing in Braun A, Pellicci DG, Godfrey DI, Belz GT, Pellegrini M, Gebhardt T, Busslinger M, Shi W, Carbone FR, non-lymphoid tissues. His group published several key studies in leading journals of the field, including van Lier RAW, Kallies A*, van Gisbergen KPJM* 2016. Hobit and Blimp1 instruct a universal transcrip- Science, Immunity and Nature Immunology, which detail the roles of transcription factors and cytokines tional program of tissue-residency in lymphocytes. Science 352, 459-463. *co-senior authors in differentiation, clonal expansion and cellular metabolism of lymphocytes. (232 cites). The research of the Kallies laboratory focuses on the molecular control of CD8+ cytotoxic and regulato- ry T-cell differentiation with a focus on populations residing in non-lymphoid tissue, including healthy 5. Man K, Gabriel SS, Liao Y, Gloury R, Preston S, Henstridge DC, Pellegrini M, Zehn D, Berberich-Siebelt tissues and tumors. F, Febbraio MA, Shi W, Kallies A 2017. IRF4 promotes T cell exhaustion and limits the development of memory-like T cells during chronic infection. Immunity 47, 1129-1141 (44 cites).

ABSTRACT

Lymphocyte differentiation is a strictly controlled process that is critical for both immunity and ho- meostasis. My lab studies the molecular control of lymphocyte differentiation in response to antigen, including that of B cells as well as conventional and regulatory T cells. My group has developed and ap- plied genetic and molecular approaches to the field, including novel reporter mouse strains, metabolic NOTES and transcriptional profiling, chromatin immunoprecipitation (ChIP) and accessible chromatin (ATAC) sequencing. These studies detailed the roles of key transcription factors and cytokines in differentiati- on, clonal expansion and cellular metabolism of lymphocytes. Over the last years, my lab has developed a focus on the molecular control of lymphocyte populations residing in non-lymphoid tissue, including tumours. This includes studies on the central role of IL-33 in the differentiation of tissue-resident regu- latory T cells, the essential functions of transcriptional regulators Blimp1 and Hobit in the generation of tissue-resident memory T cells and the molecular control of exhausted T cells. In my presentation I will discuss recent discoveries related to the differentiation of regulatory T cells in non-lymphoid T cells and to the maintenance of effector T cells during chronic infection and in tumours. 20 | | 21 Gioacchino Natoli Session 2 “Accessibility and usage of the genomic regulatory information in immune responses”

Biochemistry, School of Medicine, 5 SELECTED PUBLICATIONS Humanitas University Milan, Italy 1. Cooptation of tandem DNA repeats for the maintenance of mesenchymal identity (C. Balestrieri, G. Alfarano, M. Milan, V. Tosi, E. Prosperini, P. Nicoli, A. Palamidessi, G. Scita, G.R. Diaferia, G. Natoli). Cell 173:1150-1164 (2018) BIOSKETCH 2. Opposing macrophage polarization programs show extensive epigenomic and transcriptional I am currently Professor of Biochemistry at the School of Medicine of Humanitas University, Milan, whe- cross-talk (Piccolo V., Curina A, Genua M, Ghisletti S, Simonatto M, Sabo‘ M, Amati B, Ostuni R, Natoli re I moved three years ago. Previously I have been working as Principal Investigator at the European G). Nature Immunology 18, 530-540. PMID 28288101 (2017). Institute of Oncology (IEO) in Milan (06/2005 to 07/2016) and at the Institute for Research in Biomedicine (IRB, Bellinzona, Switzerland) (06/2000 to 06/20005). 3. Latent enhancers activated by stimulation in differentiated cells (Ostuni R, Piccolo V, Barozzi I, Pol- I was trained as an MD at the University of Rome, where I also obtained my Residency in Internal Medi- letti S, Termanini A, Bonifacio S, Curina A, Prosperini E, Ghisletti S, Natoli G.) Cell. 152: 157-71 (2013). cine (1997) before moving to the University of California San Diego (UCSD) for a postdoctoral training in Michael Karin’s lab. 4. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages (S. Ghisletti, I. Barozzi, F. Mietton, S. Polletti, F. De Santa, E. Venturini, L. Gregory, L. Lonie, A. Chew, C.L. Wei, J. Ragoussis, G. Natoli) Immunity, 32:317-28. Epub 2010 Mar 4 ABSTRACT (2010).

Macrophage gene expression programs and cis-regulatory networks are specified by the interplay bet- 5. The histone H3 lysine 27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated ween a hardwired differentiation program that underlies macrophage identity and tissue micro-en- gene silencing (F. De Santa, M.G. Totaro, E. Prosperini, S. Notarbartolo, G. Testa and G. Natoli). Cell vironmental signals that influence the distinctive properties acquired by these cells in different tissues. 130, 1083-1094 (2007). Exposure to a variety of danger signals, including molecules released from damaged tissues and mo- lecules associated with -or released by- invading microbes, induces dramatic changes in macrophage gene expression programs and eventually functional properties. The correct and efficient deployment of such programs is essential both to cope with threats to organism survival and to restore homeost- asis. Data obtained in the last years allowed understanding the mechanisms controlling macropha- ge-specific gene expression programs in response to micro-environmental and danger signals. It is now clear that lineage determining transcription factors that specify macrophage differentiation such as PU.1 and IRF8, set the stage for the activity of signal-regulated transcription factors. This entails the constitutive displacement of nucleosomes that occlude genomic regulatory elements required for macrophage-specific gene regulation as well as the cooperation with signal-regulated transcription factors in order to remodel chromatin in response to stimulation and thus enable the stimulus-specific NOTES expansion of the accessible repertoire of genomic regulatory elements.

22 | | 23 Tal Arnon Session 2 “Perivascular pathways direct one-way migration of T cells into splenic T zones”

Wellcome Trust Investigator and Senior Kennedy Research Fellow 5 SELECTED PUBLICATIONS at the Institute of Rheumatology, University of Oxford 1. Chauveau A, Pirgova G, Cheng HW, De Martin A, Zhou FY, Wideman S, Rittscher J, Ludewig B, and Arnon TI. Perivascular pathways direct one-way migration of T cells into splenic T zones. Under revision (Immunity) BIOSKETCH 2. Reboldi A, Arnon TI, Rodda LB, Atakilit A, Sheppard D and Cyster JG. B cell interaction with subepithe- Dr Tal Arnon PhD is a Wellcome Trust Investigator and a Senior Kennedy Research Fellow at the Institute lial dendritic cells in Peyer‘s patches is critical for IgA production. (2016) Science 352(6287):aaf4822. of Rheumatology, Oxford. She obtained a PhD from The Hebrew University (2005) and was trained a JIF: 41.06 .Citation: 71. postdoctoral Fellow with Professor Jason Cyster in UCSF, before joining the University of Oxford in 2014. Her research focuses on understanding basic mechanisms that regulate lymphocyte trafficking and B 3. Arnon TI, Horton BM, Grigorova IL and Cyster JG. Visualization of splenic marginal zone B cell cell responses. shuttling and follicular B cell egress. (2013) Nature 493(7434):684-8. Citation: 103, JIF: 41.456, PMID: 23263181.

ABSTRACT 4. Arnon TI, Xu Y, Lo C, Pham T, An J, Coughlin S, Dorn GW, Cyster JG. GRK2-dependent S1PR1 desensitiza- tion is required for lymphocytes to overcome their attraction to blood. (2011) Science 333: 1898-903. Lymphocyte homeostasis and immune surveillance require that naïve T and B cells continuously re- Citation: 103, JIF: 41.06, PMID: 21960637. circulate between secondary lymphoid organs. While the mechanisms of lymphocyte entry into lymph nodes has been intensely studied, the manner by which cells traffic within the spleen, the largest of the 5. Arnon TI et al. Inhibition of the NKp30 activating receptor by pp65 of human cytomegalovirus. secondary lymphoid organs, is poorly defined. Here, using intravital microscopy, we reveal unexpected (2005). Nature Immunology 6: 515-23. Citation: 259, JIF: 21.80, PMID: 15821739. routes and mechanisms used by T cells to enter splenic T zones. We demonstrate that upon initial release in the marginal zone (MZ) and red pulp, T cells join well defined paths that lead them to the bridging channels and connect them directly to T zones. We further show that these paths are formed by vascular structures that act as scaffolds guiding cellular migration in a one-directional manner exclusively towards T zones but not away from them, indicating the existence of distinct entry and exit routes. Examining patterns of cell behaviour during entry further revealed a requirement for a yet unidentified G-protein coupled receptor (GPCR) that is needed for attachment to the entry paths and the existence of a checkpoint located at the gate to the T zone. Taken together, our study uncovers previously unappreciated routes of T cell migration in the spleen, revealing unique structural organiz- ation and mechanisms that evolved to support lymphocyte recirculation via this large systemic organ.

NOTES

24 | | 25 Andreas Radbruch Session 3 “Cellular Pathology of Chronic Inflammatory Diseases”

Professor of Rheumatology and Scientific Director 5 SELECTED PUBLICATIONS Deutsches Rheuma-Forschungszentrum (DRFZ), ein Leibniz Institut Berlin 1. Hradilkova K, Maschmeyer P, Westendorf K, Schliemann H, Husak O, von Stuckrad ASL, Kallinich T, Minden K, Durek P, Grün JR, Chang HD, Radbruch A. Regulation of Fatty Acid Oxidation by Twist 1 in the Metabolic Adaptation of T Helper Lymphocytes to Chronic Inflammation.Arthritis Rheumatol. BIOSKETCH 2019 Oct;71(10):1756-1765.

Andreas Radbruch is Scientific Director of the DRFZ and Professor of Rheumatology at the Charité 2. Tokoyoda K, Zehentmeier S, Hegazy AN, Albrecht I, Grün JR, Löhning M, Radbruch A. Professional Medical School. His recent work addresses the basic organisation of immunological memory, its com- memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow. Immunity. 2009 partmentalisation and maintenance, in particular of bone marrow-resident immune memory cells. He May;30(5):721-30. has originally described long-lived memory plasma cells and stromal cell niches for immune memory cells. He has developed therapeutic strategies for the ablation of (memory) plasma cells secreting pa- 3. Manz RA, Thiel A, Radbruch A. Lifetime of plasma cells in the bone marrow. Nature. 1997 Jul thogenic antibodies. Based on earlier work on the epigenetic and transcriptional imprinting of memory 10;388(6638):133-4. T cells, he has identified molecular adaptations of T cells to chronic inflammation, e.g. the transcription factor Twist1, as novel targets for their selective ablation. 4. Jung S, Rajewsky K, Radbruch A. Shutdown of class switch recombination by deletion of a switch Andreas Radbruch did his PhD at the Genetics Institute of Cologne University with Klaus Rajewsky. His region control element. Science. 1993 Feb 12;259(5097):984-7. early work on antibody class switching has revealed transcriptional targeting of class switch recom- bination by (T cell derived) cytokines, and instruction and selective epigenetic imprinting of cytokine 5. Miltenyi S, Müller W, Weichel W, Radbruch A. High gradient magnetic cell separation with MACS. genes in T cells. He has pioneered (cytometric) single cell technologies, in particular the cytometric Cytometry. 1990;11(2):231-8. secretion assay and the MACS technology. He has been President of the German Societies for Rheu- matology and for Immunology, and the International Society for Advancement of Cytometry (ISAC). He is President of the European Federation of Immunological Societies (EFIS). He received the Carol Nachman Prize for Rheumatology and the Avery Landsteiner Award for Immunology.

ABSTRACT

In refractory patients with chronic inflammatory diseases, therapy-free remission can be achieved by resetting the immune system, i.e. ablating immune cells and regenerating the immune system from stem cells. This identifies experienced and imprinted immune cells as essential and sufficient drivers of inflammation. The “dark side” of immunological memory involves memory plasma cells secreting pathogenic antibodies, and T lymphocytes secreting pathogenic cytokines and chemokines. Single cell-transcriptomes of T cells from the inflamed joints of patients with juvenile idiopathic arthritis NOTES reveal cognate activation of these cells in situ. They are refractory to conventional therapies, which aim at the suppression of chronic immune reactions, rather than the maintenance of pathogenic ef- fector cells. Innovative therapeutic strategies can be developed from a molecular understanding of the rules governing their persistence. Here we have identified a key role for mesenchymal stromal cells, preventing metabolic stress-induced apoptosis by induction of PI3K signalling in memory cells. T helper lymphocytes driving chronic inflammation also depend on the transcription factors T-bet and Twist1, to downregulate the pro-apoptotic protein Bim by induction of microRNA 148a, and to force the cells to use fatty acid oxidation, i.e. allow their survival in inflamed tissues. Twist1 is a master regulator of adaptation of pathogenic T helper lymphocytes to chronic inflammation. Genes regulated by it, in 26 | particular miR148a, are promising new therapeutic targets. | 27 Chiara Romagnani Session 3 “Innate checkpoints of inflammation”

Charité - Universitätsmedizin Berlin (CBF) Med. Klinik m.S. Gastroenterologie, Infektiologie und Rheumatologie 5 SELECTED PUBLICATIONS and Deutsches Rheuma-Forschungszentrum (DRFZ), ein Leibniz Institut Berlin 1. Hammer Q, Rückert T, Borst EM, Dunst J, Haubner A, Durek P, Heinrich F, Gasparoni G, Babic M, Tomic A, Pietra G, Nienen M, Blau IW, Hofmann J, Na IK, Prinz I, Koenecke C, Hemmati P, Babel N, Arnold R, Walter J, Thurley K, Mashreghi MF, Messerle M, Romagnani C. Peptide-specific recognition of human BIOSKETCH cytomegalovirus strains controls adaptive natural killer cells. Nat Immunol. 2018 May;19(5):453- 463. doi: 10.1038/s41590-018-0082-6. Epub 2018 Apr 9. Chiara Romagnani is currently DFG-Heisenberg Professor at the Charité Universitätsmedizin and group leader at the DRFZ. Her team focuses primarily on innate immunity and on investigating how innate 2. Luetke-Eversloh M, Hammer Q, Durek P, Nordström K, Gasparoni G, Pink M, Hamann A, Walter J, lymphoid cells (ILC), especially Natural Killer (NK) cells, respond during inflammatory responses. Her Chang HD, Dong J and Romagnani C. Human Cytomegalovirus Drives Epigenetic Imprinting of the recent work has identified the role of innate receptors in driving activation of ILCs and modulating T IFNG Locus in NKG2Chi Natural Killer Cells. PLoS Pathog. 2014 Oct 16;10(10):e1004441. cell effector functions, thereby serving as immune checkpoints to modulate chronic inflammation. She received her MD degree from the University of Florence, Italy. After training as oncologist, she 3. Juelke K, Killig M, Luetke-Eversloh M, Parente E, Gruen J, Morandi B, Ferlazzo G, Thiel A, Schmitt-Kno- obtained in 2006 a PhD in Immunology from the University of Genova under the supervision of Lorenzo salla I, Romagnani C. CD62L expression identifies a unique subset of polyfunctional CD56dim NK Moretta. With an EMBO fellowship, she moved to Berlin and trained as a postdoc at the Deutsches Rheu- cells. Blood. 2010; Aug 26;116(8):1299-307. ma Forschungszentrum (DRFZ), Berlin, Germany. 4. Montaldo E, Teixeira-Alves LG, Glatzer T, Hamann W, Babic M, Paclik D, Stölzel K, Gröne J, Lozza L, Juelke K, Matzmohr N, Loiacono F, Petronelli P, Huntington ND, Moretta L, Mingari MC and Roma- ABSTRACT gnani C. Human RORγt+ CD34+ cells are lineage-specified progenitors of group 3 RORγt+ innate lymphoid cells. Immunity. 2014 Dec 18;41(6):988-1000. Chronic inflammatory disorders can be triggered and maintained by effector mediators produced by experienced immune cells, such as T cell and B cells. In T cells, inflammatory programs are induced by 5. Glatzer T, Killig M, Meisig J, Ommert I, Luetke-Eversloh M, Babic M, Paclik D, Blüthgen N, Seidl R, the T cell receptor (TCR) in conjunction with distinct cytokines and/or environmental signals. Innate Seifarth C, Gröne J, Lenarz M, Stölzel K, Fugmann D, Porgador A, Hauser A, Karlas A, Romagnani C. lymphoid cells (ILCs), including NK cells, exhibit a similar heterogeneity of effector modules, which are RORγt+ innate lymphoid cells acquire a proinflammatory program upon engagement of the activa- activated in the course of inflammation in a TCR-independent manner. The signals and innate receptors ting receptor NKp44. Immunity. 2013 Jun 27;38(6):1223-35. instructing the imprinting of different effector programs and their execution in ILCs remain largely unknown. We have studied the innate modules and triggers employed by ILCs, and shared by T cells, which can contribute to promote inflammatory responses in a TCR-independent fashion.

NOTES

28 | | 29 Georg Schett Session 3 “Towards a molecular profiling of inflammatory disease”

Professor of Internal Medicine 5 SELECTED PUBLICATIONS Head of Department Department of Medicine 3 – Rheumatology and Immunology 1. Culemann S, Grüneboom A, Nicolás-Ávila JÁ, Weidner D, Lämmle KF, Rothe T, Quintana JA, Kirchner Friedrich-Alexander University Erlangen-Nürnberg, Germany P, Krljanac B, Eberhardt M, Ferrazzi F, Kretzschmar E, Schicht M, Fischer K, Gelse K, Faas M, Pfeifle R, Ackermann JA, Pachowsky M, Renner N, Simon D, Haseloff RF, Ekici AB, Bäuerle T, Blasig IE, Vera J, Voehringer D, Kleyer A, Paulsen F, Schett G, Hidalgo A, Krönke G. (2019) Locally renewing resident BIOSKETCH synovial macrophages provide a protective barrier for the joint. Nature. 572(7771):670-675. Epub 2019 Aug 7. Georg Schett is professor of Internal Medicine and since 2006 head of the Department of Medicine 3 - Rheumatology and Immunology – of the Friedrich-Alexander University Erlangen-Nürnberg in Germany. 2. Wohlfahrt T, Rauber S, Uebe S, Luber M, Soare A, Ekici A, Weber S, Matei AE, Chen CW, Maier C, Ka- Prof. Schett graduated from the University of Innsbruck (Austria) in 1994. After his dissertation from rouzakis E, Kiener HP, Pachera E, Dees C, Beyer C, Daniel C, Gelse K, Kremer AE, Naschberger E, Stürzl medical school, he worked as scientist at the Institute of BioMedical Aging Research of the Austrian M, Butter F, Sticherling M, Finotto S, Kreuter A, Kaplan MH, Jüngel A, Gay S, Nutt SL, Boykin DW, Poon Academy of Science in Innsbruck. In 1996, he joined the Department of Medicine at the University of GMK, Distler O, Schett G, Distler JHW, Ramming A. (2019) PU.1 controls fibroblast polarization and Vienna, where he completed his postgraduate training in Internal Medicine and subsequently in Rheu- tissue fibrosis. Nature. 566(7744):344-349. Epub 2019 Jan 30. matology. In 2003 he was promoted to professor of Internal Medicine. Before taking up his position as chair of the Department of Medicine 3, he worked as a scientist in the United States for one year. 3. Palumbo-Zerr K, Zerr P, Distler A, Fliehr J, Mancuso R, Huang J, Mielenz D, Tomcik M, Fürnrohr BG, His scientific work focuses on creating a better understanding of the molecular basis of immune-in- Scholtysek C, Dees C, Beyer C, Krönke G, Metzger D, Distler O, Schett G, Distler JH. (2015) Orphan flammatory diseases with rapid translation into clinical practice. Initially, he investigated the immuno- nuclear receptor NR4A1 regulates transforming growth factor-β signaling and fibrosis.Nat Med. logy of atherosclerosis and focused on antibody-mediated endothelial cell damage. His research work 21(2):150-8. Epub 2015 Jan 12. lead to the understanding of the phenomenon of LE-cells in 2007. He was awarded the renowned START Award in 2002 and founded a research group for arthritis in Vienna. Prof. Schett is an ERC award winner 4. Schauer C, Janko C, Munoz LE, Zhao Y, Kienhöfer D, Frey B, Lell M, Manger B, Rech J, Naschberger E, and speaker of several DFG- and BMBF-funded joint projects. His work has been awarded numerous Holmdahl R, Krenn V, Harrer T, Jeremic I, Bilyy R, Schett G, Hoffmann M, Herrmann M. (2014) Agg- prizes, including the Carol Nachman Prize, and published in over 650 scientific articles. regated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat Med. 20(5):511-7. Epub 2014 Apr 28.

5. McInnes IB, Schett G. (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med. 365(23):2205- 19. Review. No abstract available.

NOTES

30 | | 31 Dietmar Zehn Session 3 “InTOXication causes T-cell exhaustion in chronic infection”

Full Professor – Chair, Division of Animal Physiology and Immunology School of Life Sciences Weihenstephan 5 SELECTED PUBLICATIONS Technical University of München 1. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, Roelli P, Utzschneider DT, von Hoesslin M, Cullen JG, Fan Y, Eisenberg V, Wohlleber D, Steiger K, Merkler D, Delorenzi M, Knolle PA, Cohen CJ, Thimme R, Young- BIOSKETCH blood B, Zehn D. Nature. 2019 Jul;571(7764):265-269. doi: 10.1038/s41586-019-1326-9. Epub 2019 Jun 17. since 10/2015 Full Professor – Chair, Technical University Munich Area of expertise: Molecular and cellular mechanisms underlying T-cell 2. High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell exhaustion in chronic infections and tumors, Effector and memory T-cell expansion and survival. Utzschneider DT, Alfei F, Roelli P, Barras D, Chennupati V, Darbre S, differentiation, Immune tolerance, Autoimmune diseases Delorenzi M, Pinschewer DD, Zehn D. J Exp Med. 2016 Aug 22;213(9):1819-34. doi: 10.1084/jem.20150598. Epub 2016 Jul 25. 2010-2015 Assistant Professor, Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland 3. T Cell Factor 1-Expressing Memory-like CD8(+) T Cells Sustain the Immune Response to Chronic Viral 2009-2010 Research Group Leader Division of Immunology and Allergy, Centre Infections. Utzschneider DT, Charmoy M, Chennupati V, Pousse L, Ferreira DP, Calderon-Copete S, Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland Danilo M, Alfei F, Hofmann M, Wieland D, Pradervand S, Thimme R, Zehn D*, Held W.* Immunity. 2016 Aug 16;45(2):415-27. doi: 10.1016/j.immuni.2016.07.021. Equal contribution at senior level 2004-2009 Senior Research Fellow, laboratory of Prof. Michael J. Bevan, Howard Hughes Medical Institute / Department of Immunology, University of 4. T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion. Washington, Seattle, USA Utzschneider DT, Legat A, Fuertes Marraco SA, Carrié L, Luescher I, Speiser DE, Zehn D. Nat Immu- 2004 Graduate (doctorate) student, Prof. Peter Walden, Department of nol. 2013 Jun;14(6):603-10. doi: 10.1038/ni.2606. Epub 2013 May 5. Dermatology, Charité, Berlin, Germany 5. Complete but curtailed T-cell response to very low-affinity antigen. Zehn D, Lee SY, Bevan MJ. 1996-2004 Charité – Medical School of the Humboldt University Berlin, Germany Nature. 2009 Mar 12;458(7235):211-4. doi: 10.1038/nature07657. Epub 2009 Jan 28.

ABSTRACT

Persisting viral infection and cancer can induce a T-cell phenotype known as “exhaustion”. It is cha- racterized by low cytokine production and up-regulated expression of inhibitory receptors and results in a less potent effector response compared to T-cells found in acute infections. From a therapeutic perspective, it is critically important to understand and overcome the transcriptional networks that NOTES induce and maintain the “exhausted” phenotype. Several molecules were shown to impact T-cells in chronic infection but none of which act exclusively in chronic infection. We have recently identified that the thymocyte selection-associated high mobility group-box protein (Tox) serves an exclusive role in inducing the exhausted phenotype. While its absence did not impair activation, expansion, and memo- ry-formation of T-cells in acute infection, Tox deficient T-cells retained an acute phenotype in chronic infections. This involved decreased levels of inhibitory receptor expression, more effective virus cont- rol, and a significantly augmented level of immunopathology. Moreover, Tox is critical for maintaining the Tcf-1 positive progenitor T-cell pool. Tcf-1+ T-cells declined rapidly without Tox and, as a consequen- ce, the entire population was rapidly depleted. Overall, we have established that Tox is a key transcrip- 32 | tion factor that reinforces the phenotype and longevity of exhausted T-cells in chronic viral infection. | 33 Claudia Waskow Session 3 “Generation and Regeneration of Hematopoietic Stem Cells”

Institute of Aging, 5 SELECTED PUBLICATIONS Friedrich-Schiller University, Jena, Germany www.WaskowLab.com 1. Jacome-Galarza CE*, Percin GI*, Mueller JT*, Mass E*, Lazarov T, Eitler J, Rauner M, Yadav V, Crozet L, Bohm M, Karsenty G, Waskow C$ and Geissmann F$. 2019 Developmental origin and functional maintenance of osteoclasts. Nature, 568:541-545. IF41.6, *same contribution first author, $co-su- BIOSKETCH pervised the study

The Waskow laboratory concentrates on fundamental aspects of hematopoietic stem cell biology in- 2. Percin GI*, Eitler J*, Kranz A, Fu J, Pollard JW, Naumann R, and Waskow C. 2018 CSF1R regulates cluding the regulation of fate decisions determining stem cell pool size, heterogeneity, differentiation, the dendritic cell pool size in adult mice via embryo-derived tissue-resident macrophages. Nature and oncogenic transformation. Our research, although basic science in nature, will provide results that Comms, 11;9(1):5279. IF12.4, *same contribution first author can be extended to the modulation of human hematopoiesis for the treatment of hematological disease and trauma. 3. Arndt K, Kranz A, Fohgrub J, Jolly A, Bledau AS, Di Virgilio M, Lesche M, Dahl A, Höfer T, Stewart AF, Dr. Waskow performed her thesis studies at the prestigious Basel Institute for Immunology and received and Waskow C. 2018. SETD1A protects HSCs from activation-induced functional decline in vivo. Blood her PhD from Basel University. During her postdoctoral phase at Ulm University she published on the 131(12):1311-1324. IF13.17 role of growth factor receptors in hematopoiesis and on the generation of ‚universal recipient mice‘ that accept allogeneic hematopoietic stem cells. After moving to the Rockefeller University in New York, 4. Cosgun* KN, Rahmig* S, Mende N, Reinke S, Hauber I, Schäfer C, Petzold A, Weisbach H, Heidkamp G, USA, Dr. Waskow could answer long-standing questions on immune cell turn over and hematopoietic Purbojo A, Cesnjevar R, Platz A, Bornhäuser M, Schmitz M, Dudziak D, Hauber J, Kirberg J, Waskow progenitor cell transit though the blood. In 2008, Dr. Waskow started her own group at the Technical C, 2014. Kit Regulates HSC Engraftment across the Human-Mouse Species Barrier. Cell Stem Cell, University Dresden, where she focused on the regulation of hematopoietic stem cell function of mice 15:227-238. * same contribution first author, IF25.91 and humans to modulate their maintenance, engraftment, and transformation in vivo. This work re- sulted in a number of publications in highly visible journals, and in 2014 Dr. Waskow was promoted to 5. Grinenko T, Arndt K, Portz M, Mende N, Günther M, Cosgun KN, Alexopoulou D, Lakshmanaperumal N, Professor for Immunology in Dresden. Her laboratory recently moved to the Leibniz Institute on Aging Henry I, Dahl A, Waskow C, 2014. Clonal expansion capacity defines two consecutive developmental in Jena, where she concentrates her scientific program on the regulation of hematopoietic stem cell stages of long-term hematopoietic stem cells. J Exp Med. 211:209-215. IF13.91 function, hematopoiesis and immune biology in the aging organism.

ABSTRACT

The aim of our studies is the identification of cell-autonomous and -extrinsic factors governing main- tenance of hematopoietic stem cells, differentiation, and function of immune cells from mice and hu- mans. This includes the understanding of immune cell homeostasis during steady state and under inflammatory conditions from the embryo to the aged organism. We focus on molecular and cellular NOTES mechanisms determining fate decisions of hematopoietic stem and progenitor cells using innovative mouse models suitable for the engraftment of human and mouse hematopoietic stem and progenitor cells established in our laboratory, high-resolution gene expression analysis, combined with quantita- tive single cell transplantations, functional genomics, and mathematic modeling to understand mecha- nisms of HSPC pool size control. I will present an overview about our current research on regulatory pathways important for hematopoietic stem cell maintenance and hematopoiesis in vivo and on the cross-communication between immune cells of distinct developmental origins. The research of my la- boratory, thus, focuses on uncovering fundamental mechanisms that regulate hematopoietic stem cell and immune cell biology to create the basis for new groundbreaking discoveries in mechanistic biome- 34 | dicine as a way to improve health throughout life. | 35 Hans-Dieter Volk Session 4 “Translational immunology – from pathogenesis to new diagnostics and therapies”

Charité - Universitätsmedizin Berlin: Institute for Medical Immunology and - Epigenetic regulation and editing of T-cell functions Berlin Institute of Health (BIH): BIH Center for Regenerative Therapies - Impact of immune balance on challenged tissue homeostasis (BCRT) and Labor Berlin Charité Vivantes: Dept. of Immunology - Immunogenicity – challenge for gene therapy including gene editing

This translational concept will be explained in more detail using 1-2 examples. BIOSKETCH

HDV is W3 professor for “Immunolgy and Regeneration” at the Charité. He is head of the Institute of 5 SELECTED PUBLICATIONS Medical Immunology, and the BIH- Center for Regenerative Therapies (BCRT), and the Dept.Immunology of Labor Berlin Charité Vivantes GmbH. 1. Wagner DL, Amini L, Wendering DJ, Burkhardt LM, Akyüz L, Reinke P, Volk HD*, Schmueck-Henneresse He is strongly committed for Translational Immunology with research focus on Regeneration and Immu- M*. High prevalence of Streptococcus pyogenes Cas9-reactive T cells within the adult human popu- nology, Transplantation, Infections, and Cell Therapy. He is coordinating the EU-supported international lation. Nat Med. 2019 Feb;25(2):242-248. doi: 10.1038/s41591-018-0204-6. Epub 2018 Oct 29. research consortia, PACE (phase 3 cell therapy study: pace-h2020.eu) and RESTORE-Health by Advanced Therapies (restore-horizon.eu), and is member of the steering committees of ReSHAPE undesired im- 2. Volk HD, Stevens MM, Mooney DJ, Grainger DW, Duda GN. Key elements for nourishing the transla- mune reactions by next generation Treg (reshape-h2020.eu) and HIPGEN (phase 3 cell therapy study: tional research environment. Sci Transl Med. 2015 Apr 8;7(282):282cm2. doi: 10.1126/scitranslmed. hipeen.eu). Several research projects could be translated to diagnostics on the market. Several biotech aaa2049. companies were founded as spin-offs from the Inst.Med.Immunlogy and BCRT. HDV studied Medicine from 1974-80 and received his MD at 1982 from the Humboldt-University in Berlin 3. Reinke S, Geissler S, Taylor WR, Schmidt-Bleek K, Juelke K, Schwachmeyer V, Dahne M, Hartwig T, focussing on transplantat immunology. After completing his medical specialist training in Immunology, Akyüz L, Meisel C, Unterwalder N, Singh NB, Reinke P, Haas NP, Volk HD*, Duda GN*. Terminally diffe- he became head of the clinical immunology department at the Inst.Med.Immunology of the Charite in rentiated CD8+ T cells negatively affect bone regeneration in humans. Sci Transl Med. 2013 Mar 20; 1987. From 1987-92 he worked part-time as fellow in the Inst Immunology at the FU Berlin (head: Tibor 5(177):177ra36. doi: 10.1126/scitranslmed.3004754. Diamantstein). Since 1993 he is leading the Inst.Med.Immunology and since 2006 the translational cen- ter BCRT. 4. Meisel C, Schefold JC, Pschowski R, Baumann T, Hetzger K, Gregor J, Weber-Carstens S, Hasper D, Keh D, Zuckermann H, Reinke P, Volk HD. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-con- ABSTRACT trolled multicenter trial. Am J Respir Crit Care Med. 2009 Oct 1;180(7):640-8. doi: 10.1164/rc- cm.200903-0363OC. Epub 2009 Jul 9. The lecture should give a short overview of the immunological research at Institute of Medical Immu- nology and BCRT. 5. Kern F, Surel IP, Brock C, Freistedt B, Radtke H, Scheffold A, Blasczyk R, Reinke P, Schneider-Mer- Our mission is translational immunology from basic research to new diagnostics and therapies. gener J, Radbruch A, Walden P, Volk HD. T-cell epitope mapping by flow cytometry.Nat Med. 1998 To achieve this, we have created interdisciplinary structures with partner clinics and institutes. Initially, Aug;4(8):975-8 the focus was on transplantation and infection immunology, more recently also on immunodeficien- cies, autoimmunity, chronic fatigue syndrome, and regenerative medicine. In the field of regenerative therapies (including cell therapies), new structures such as BCRT and BeCAT have emerged, where im- NOTES munology and regeneration including cell therapies play a central role. Thus, completely new concepts up to innovative diagnostic/therapeutic approaches could be developed during the last decades, e.g:

- Immunoparalysis in critically ill patients - Risk assessment and targeted immunotherapy of viral infections in immunocompromised patients - Reshaping undesired immune reactions by regulatory T cells - Chronic Fatigue Syndrome and Autoimmunity 36 | - Primary immunodeficiencies in adults | 37 Julia Polánsky-Biskup Session 4 “Utilizing epigenetics for the benefit of Advanced Therapies”

Charité - Universitätsmedizin Berlin, BCRT-Berlin Institute of Health Center 5 SELECTED PUBLICATIONS for Regenerative Therapies and Deutsches Rheuma-Forschungszentrum – DRFZ, ein Institut der Leibniz-Gemeinschaft 1. Szilagyi BA, Triebus J, […] Polansky JK*, Hamann A* (2017). Expression of the gut homing receptor integrin α4β7 is stably imprinted in CD4+ memory T cells by epigenetic modification of regulatory regions in the itga4 locus. *shared last authorship. Mucosal Immunology, doi: 10.1038/mi.2017.7. BIOSKETCH 2. Durek P, Nordström K, Gasparoni G, Kressler C, de Almeida M, Salhab A, […] Polansky JK. (2016) JPB is heading a research group at the ‚Berlin Institute of Health Center for Regenerative Therapies Epigenomic Profiling of Human CD4+ T Cells Supports a Linear Differentiation Model and Highlights (BCRT)‘ at the Charité Universitätsmedizin Berlin, and at the Leibniz institute ‚German Rheumatism Re- Molecular Regulators of Memory Development. Immunity, 45, 1148-1161. search Centre (DRFZ)‘. She was recruited as a professor to the Charité in 06/2019 and became a member of the steering committee of the BCRT. Her group focuses on the clarification of epigenetic mechanisms 3. Polansky JK, et al (2010). Methylation matters: Binding of Ets-1 to the demethylated Foxp3 gene which contribute to the differentiation, aging and function of immune cells with a special focus on DNA contributes to the stabilization of Foxp3 expression in regulatory T cells. J Mol Med. Oct;88(10):1029- methylation and T lymphocytes. For this, the group generates, analyzes and interprets genome-wide 40. as well as gene-specific epigenetic profiles of primary human T cell populations during health and under diseased conditions. These data sets allow the definition of cell type-specific epigenetic switch 4. Huehn J, Polansky JK, Hamann A. (2009). Epigenetic control of FOXP3 expression: the key to a regions which might serve a diagnostic biomarkers but at the same time represent promission target stable regulatory T-cell lineage? Nat Rev Immunol. Feb;9(2):83-9. structures for precise epigenetic editing methods for the directed manipulation of cellular phenotypes for therapeutic approaches. 5. Polansky JK, Kretschmer K, Freyer J, Floess S, Garbe A, Baron U, Olek S, Hamann A, von Boehmer H, JPB received her PhD from the Humboldt-University in Berlin already focussing on the epigenetic re- Huehn J (2008). DNA methylation controls Foxp3 gene expression. Eur J Immunol. 38(6):1654-63. gulation of regulatory T cells. She has worked in several academic research institutions, including the Helmholtz Centre for Infection Research in Braunschweig and the Dana-Farber Cancer Institute at Harvard Medical School in Boston, USA.

ABSTRACT

Adoptive T cell therapy is a promising approach in various clinical settings, from fighting cancer and chronic infections to combating auto-immunity and graft rejection. For such clinical applications, the expanded T cell products need to be fit and to maintain functional stability during the production pro- cess and after transfusion into the patients. We address these required T cell features from an epigenetic viewpoint and generated genome-wide epigenetic maps for several CD4+ T cell subpopulations. These data allowed the extraction of epigenetic elements essential for the imprinting of functional T cell phenotypes (‚Epi-stabilizers‘) which might be NOTES utilized as molecular switches for the targeted induction of advantageous T cell qualities at will. To this end, we established a powerful ‚hit-and-run‘ CRISPR/Cas9-based epigenetic editing approach for the targeted demethylation of Epi-stabilizers. As a proof-of-concept, we were able to induce the immu- no-suppressive master transcription factor FOXP3 from its endogeneous locus by directed epigenetic editing in previously pro-inflammatory human T cells. The induced demethylated state was stable over weeks even after expression of the editing complex has ceased. With this we show, that epigenetic editing is suited to change the molecular profile of T cells and suggest the presented technique as a tool for improving T cell products for advanced cellular therapies.

38 | | 39 Hedda Wardemann Session 4 “Qualitative assessments of adaptive immune responses at single-cell level”

Department of B-cell Immunology 5 SELECTED PUBLICATIONS German Cancer Research Center (DKFZ) Heidelberg, Germany 1. Imkeller K, Scally SW, Bosch A, Martí GP, Costa G, Triller G, Murugan R, Renna V, Jumaa H, Kremsner PG, Sim BKL, Hoffman SL, Mordmüller B, Levashina E, Julien JP, Wardemann H. Antihomotypic affinity maturation improves human B cell responses against a repetitive epitope. Science 360:1358-1362 BIOSKETCH (2018).

2014 – present Head of Division 2. Rollenske T, Szijarto V, Lukasiewicz J, Guachalla LM, Stojkovic K, Hartl K, Stulik L, Kocher S, La- Division of B Cell Immunology sitschka F, Al-Saeedi M, Schröder-Braunstein J, von Frankenberg M, Gaebelein G, Hoffmann P, Klein German Cancer Research Center, Heidelberg, Germany S, Heeg K, Nagy E, Nagy G, Wardemann H. Cross-specificity of protective human antibodies against Klebsiella pneumoniae LPS O-antigen. Nat Immunol. 19:617-624 (2018). 2006 – 2014 Max Planck Research Group Leader Research Group Molecular Immunology 3. Murugan R, Buchauer L, Triller G, Kreschel C, Costa G, Pidelaserra Martí G, Imkeller K, Busse CE, Cha- Max Planck Institute for Infection Biology, Berlin, Germany kravarty S, Sim BKL, Hoffman SL, Levashina EA, Kremsner PG, Mordmüller B, Höfer T, Wardemann H. Clonal selection drives protective memory B cell responses in controlled human malaria infection. 2003 – 2005 Research Assistant Professor Sci Immunol. pii: eaap8029 (2018). Laboratory of Molecular Immunology, Head: Michel Nussenzweig The Rockefeller University, New York, USA 4. Triller G, Scally SW, Costa G, Pissarev M, Kreschel C, Bosch A, Marois E, Sack BK, Murugan R, Salman AM, Janse CJ, Khan SM, Kappe SHI, Adegnika AA, Mordmüller B, Levashina EA, Julien JP, Wardemann 2001 – 2003 Postdoctoral Associate H. Natural Parasite Exposure Induces Protective Human Anti-Malarial Antibodies. Immunity 47:1197- Laboratory of Molecular Immunology, Head: Michel Nussenzweig 1209 (2017). The Rockefeller University, New York, USA 5. Zimmermann N, Thormann V, Hu B, Köhler AB, Imai-Matsushima A, Locht C, Arnett E, Schlesinger LS, Zoller T, Schürmann M, Kaufmann SH, Wardemann H. Human isotype-dependent inhibitory antibody ABSTRACT responses against Mycobacterium tuberculosis. EMBO Mol. Med. 8:1325-1339 (2016).

Single cell Ig gene amplification and sequencing is increasingly used for the molecular assessment of adaptive antigen receptor repertoires. We have developed a platform for the high-throughput analysis of human and mouse Ig gene repertoires that preserves natural IgH and IgL gene associations and provides full-length Ig gene sequence information for direct gene cloning and the production of recom- binant monoclonal antibodies. Recently, we have established a similar platform for the amplification and cloning of paired human and murine T cell receptor (TCR) alpha and beta chain genes to enable NOTES functional assessments of TCRs at single cell level. I will discuss how we use this platform to study the clonal evolution and functional quality of adaptive immune responses in humans, to identify anti- gen-receptors with therapeutic potential, and to develop structure-guided vaccine design strategies.

40 | | 41 Alexander Scheffold Session 4 “Antigen-specific regulation of tolerance & inflammation in humans”

Christian-Albrechts-Universität zu Kiel & Universitätsklinikum Schleswig- 5 SELECTED PUBLICATIONS Holstein, Institut für Immunologie | Arnold-Heller-Str. 3 | Haus U30 | 24105 Kiel | Tel.: 0431 500-31000, Fax: -31004 | [email protected] 1. Bacher P, Hohnstein T, Beerbaum E, Röcker M, Blango MG, Kaufmann S, Röhmel J, Eschenhagen P, Seidel K, Rickerts V, Lozza L, Stervbo U, Nienen M, Babel N, Milleck J, Assenmacher M, Cornely OA, Ziegler M, Wisplinghoff H, Heine G, Worm M, Siegmund B, Maul J, Creutz P, Tabeling C, Ruwwe-Glösen- BIOSKETCH kamp C, Sander LE, Knosalla C, Brunke S, Hube B, Kniemeyer O, Brakhage AA, Schwarz C, Scheffold A. (2019) Instruction of human anti-fungal Th17 immunity and immune pathology by cross-reactivity We are studying T cell mediated regulation of tolerance versus immunity and immune pathology in against a single member of the microbiota. Cell 176(6):1340-1355 human diseases. We developed sensitive tools for molecular and functional characterization of human T cells reacting against specific antigens relevant for diseases, such as allergy, autoimmunity or inflam- 2. Neumann C, Blume J, Roy U, Teh P, Vasanthakumar A, Beller A, Liao Y, Heinrich F, Arenzana TL, matory bowel disease. Our work contributed to the basic understanding of the antigen-specificity of Hackney JA, Eidenschenk C, Gálvez EJC, Stehle C, Heinz GA, Maschmeyer P, Sidwell T, Hu Y, Amsen D, human Treg cells and their role in allergy and the modulation of human T cell responses by intestinal Romagnani C, Chang HD, Kruglov A, Mashreghi MF, Shi W, Strowig T, Rutz S*, Kallies A*, Scheffold A*. microbota. Basic understanding of human antigen-specific immunity is a prerequisite for the develop- * (shared authorship) (2019) c-Maf-dependent regulatory T cell control of intestinal Th17 cells and ment of novel and more specific diagnostic and therapeutic approaches for human immune pathology. immunoglobulin A establishes host-microbiota homeostasis. Nat. Immunol. 20(4):471-481. After university studies in Chemistry in Freiburg and Cologne, I obtained a PhD in immunology at the University of Cologne in 1997, supervised by Andreas Radbruch. From 1997 to 2007, I established my own 3. Bacher P, Heinrich F, Stervbo U, Nienen N, Vahldieck M, Iwert C, Vogt K, Kollet J, Babel N, Sawitzki B, lab at the DRFZ Berlin focussing on the T cell mediated regulation of inflammatory disease. From 2007- Schwarz C, Bereswill S, Heimesaat MM, Heine G, Gadermaier G, Asam C, Assenmacher M, Kniemeyer 2011, I was heading a research group at Miltenyi Biotech developing new tools and GMP processes for T O, Brakhage AA, Ferreira F, Wallner M, Worm M, Scheffold A. (2016). Regulatory T cell specificity cell therapy. From 2012-2018 I was professor for cellular immunology at the Charité-Universitätsmedizin directs tolerance versus allergy against aeroantigens in humans. Cell. 167(4):1067-1078 Berlin. Since April 2018 I am the director of the Institute of Immunology at the CAU & UKSH in Kiel. 4. Bacher P, Steinbach A, Kniemeyer O, Hamprecht A, Assenmacher M, Vehreschild MJ, Vehreschild JJ, Brakhage AA, Cornely OA, Scheffold A. (2015). Fungus-specific CD4+ T cells for rapid identification ABSTRACT of invasive pulmonary mold infection. Am J Respir Crit Care Med. 191(3):348-52.

T helper cells orchestrate adaptive immunity while dysregulated T helper cell responses underlie im- 5. De la Rosa M, Rutz S. Dorninger H, Scheffold A. Interleukin-2 is essential for CD4+CD25+ regulatory mune pathologies and contribute to their chronification and treatment resistance. Despite their cen- T cell function. Eur J Immunol. 2004. 34:2480-8. tral role, the identity of the antigen-specific T cells contributing to “health” versus “pathology” is still elusive in many diseases, including allergies, autoimmunity or chronic inflammatory diseases. This is due to technical constraints and often undefined disease-relevant target antigens. In my talk I will dis- cuss our analyses of human antigen-specific T cell responses against airborne antigens and members of the intestinal microbiota as well as autoantigens. We identified antigen-specific regulatory T cells as important mediators of pulmonary tolerance and antigen escape mechanisms enabling Th2 and NOTES allergy development. Furthermore, I will discuss the impact of individual members of the microbiota on systemic T cell responses and show that T cell cross-reactivity to an intestinal commensal is a major induction mechanism for Th17 cells contributing to pulmonary inflammation in humans. Finally, the characterization of autoantigen-specific T cells identifies unique alterations in patients with autoim- mune disease. Current technological progress provides unprecedented insight into the details of human immunity and the fundamentals of human immune-mediated diseases, not necessarily predicted by animal models. Understanding these basic processes will help to clarify disease etiopathogenesis and allow develop- ment of targeted therapies. 42 | | 43 Simon Fillatreau Session 4 “Novel insights into the roles of the adaptive immune system in immune regulation and immune-mediated inflammatory diseases”

Institut Necker-Enfants Malades (INEM), INSERM U1151-CNRS UMR 8253, 5 SELECTED PUBLICATIONS Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, AP-HP, Hôpital Necker Enfants Malades, Paris, France 1. Lino AC, Dang VD, Lampropoulou V, Welle A, Joedicke J, Pohar J, Simon Q, Thalmensi J, Baures A, Flühler V, Sakwa I, Stervbo U, Ries S, Jouneau L, Boudinot P, Tsubata T, Adachi T, Hutloff A, Dörner T, Zimber-Strobl U, de Vos AF, Dahlke K, Loh G, Korniotis S, Goosmann C, Weill JC, Reynaud CA, Kauf- BIOSKETCH mann SHE, Walter J, Fillatreau S. 2018. LAG-3 Inhibitory Receptor Expression Identifies Immunosup- pressive Natural Regulatory Plasma Cells. Immunity. 49 :120-133. Our group has a longstanding interest in the role of the adaptive immune system in autoimmune and infectious diseases, which we study using pre-clinical models as well as clinical samples. Our current re- 2. Kieback, E., E. Hilgenberg, U. Stervbo, V. Lampropoulou, P. Shen, M. Bunse, Y. Jaimes, P. Boudinot, A. search combines fundamental and translational projects aiming at 1) identifying novel disease-relevant Radbruch, U. Klemm, A.A. Kühl, R. Liblau, N. Hoevelmeyer, S.M. Anderton, W. Uckert, and S. Fillatreau. pro- and anti-inflammatory B cell subsets, 2) developing novel therapeutic approaches against immu- 2016. Thymus-derived regulatory T cells are positively selected on natural self-antigen through TCR ne-mediated diseases harnessing the suppressive functions of B cells or CD4+Foxp3+ T regulatory cells, interactions of high functional avidity. Immunity. 44: 1114. 3) characterizing the interaction between lymphocytes and microorganisms at the mucosal interface, and its impact on immunological memory. 3. Shen, P., Roch, T., V. Lampropoulou, R.A. O’Connor, U. Stervbo, E. Hilgenberg, Y. Jaimes, C. Daridon, S. Fillatreau studied at Ecole Normale Supérieure de la rue d’Ulm, and did his PhD at the University R. Lui, L. Jouneau, P. Boudinot, S. Ries, Y. Miyazaki, M.D. Leech, R.C. McPherson, S. Wirtz, M. Neurath, of Edinburgh. He established the Immune Regulation research group at the Deutsches Rheuma-For- V.D. Dang, K. Hoehlig, E. Meinl, A. Grützkau, J.R. Grün, K. Horn, A.A. Kühl, T. Dörner, A. Bar-or, S.H.E. schungszentrum Berlin, a Leibniz Institute, in 2003. In 2015, he became Professor of Immunology at Kaufmann, S.M. Anderton, and S. Fillatreau. 2014. IL-35-producing B cells are critical regulators of the Medical Faculty of the University Paris Descartes. In 2014, he obtained a European Research Council immunity during autoimmune and infectious diseases. Nature. 507: 366. grant. In 2015, he was awarded the GlaxoSmithKline Stiftung Wissenschaftspreise. In 2016, he was gran- ted a long-term AXA Chair, and appointed as AXA Professor in Translational Immunology. He is editor 4. Neves, P., V. Lampropoulou, E. Calderon-Gomez, T. Roch, U. Stervbo, P. Shen, A.A. Kuhl, C. Loddenkem- for the European Journal of Immunology, deputy editor for Cellular Immunology, and review editor for per, M. Haury, S.A. Nedospasov, S.H. Kaufmann, U. Steinhoff, D.P. Calado, and S. Fillatreau. 2010. Sig- Frontiers in Immunology. naling via the MyD88 adaptor protein in B cells suppresses protective immunity during Salmonella typhimurium infection. Immunity 33:777-790.

ABSTRACT 5. Fillatreau, S., C.H. Sweenie, M.J. McGeachy, D. Gray, and S.M. Anderton. 2002. B cells regulate au- toimmunity by provision of IL-10. Nat Immunol 3:944-950 Adaptive lymphocytes are at the core of immune-mediated inflammatory diseases (IMID). The depletion of B cells can have outstanding effects in such diseases, including in those primarily T cell-mediated such as multiple sclerosis (MS). We will discuss how B cells can drive such IMID through the production of pro-inflammatory cytokines, highlighting the B cell subsets involved, and the associated molecular mechanisms. Upon differentiation into antibody-secreting cells (ASC), B cells undergo the remodeling of their cytokine expression profile, and can acquire suppressive functions. We will discuss the capacity NOTES of ASC to secrete anti-inflammatory cytokines such as interleukin-10, and to subsequently drive the complete remission from ongoing autoimmune disease. These observations underline an unsuspected diversity within the ASC compartment, and suggest the existence of distinct beneficial versus delete- rious ASC subsets in IMID. This concept is supported by our recent identification of a novel subset of natural regulatory plasma cells expressing LAG-3, PD-L1, and PD-L2. These receptors are also expressed by CD4+ T cells, which play a central role as drivers and regulators of IMID. We will present how enginee- red CD4+Foxp3+ T cells can be used to intercept IMID, and to prevent inadvertent immune reactions associated with the utilization of immune checkpoint inhibitors.

44 | | 45 Eric Vivier Session 5 “Harnessing innate immunity in cancer therapy”

Chief Scientific Officer, Head of Innate Pharma Research Laboratories immune responses in immunity, harnessing these responses opens up new possibilities for mounting Professor of Immunology, Marseille Medical School and Assistance- long-lasting, multilayered tumor control. Along these lines, we will present recent advances on the Publique des Hôpitaux de Marseille (PU-PH Classe Exceptionnelle) manipulation of an inhibitory receptor NKG2A or an activating NK cell receptor NKp46 using monoclonal antibodies and multifunctional antibodies respectively, in innovative cancer therapies. Head of the “Innate Lymphoid Cell” lab, CIML Head of the immunoprofiling lab, La Timone Hospital, Marseille Co-founder and coordinator of the Federation Hospitalo-Universtaire 5 SELECTED PUBLICATIONS Marseille-Immunopole | (http://www.marseille-immunopole.org) 1. Rankin L.C. et al., Complementarity and redundancy of IL-22-producing Innate Lymphoid cells. Na- ture Immunology, 2016, 17: 179-186. BIOSKETCH 2. Vély F. et al., Evidence of innate lymphoid cell redundancy in humans. Nature Immunology, 2016, 17: 1291-1299. Éric Vivier, DVM, PhD, is Professor of Immunology at Aix-Marseille University and at the Public Hospital 3. Crinier A. et al., Definition of Natural Killer cell heterogeneity in human and mouse by high-throug- of Marseille.Prof. Vivier was appointed Scientific Director of Innate Pharma, a biotechnology company hput single-cell RNA sequencing. Immunity, 2018, 49: 971–986. dedicated to improving cancer treatment with innovative therapeutic antibodies that exploit the im- 4. André P. et al., Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by mune system. unleashing both T and NK cells. Cell, 2018, 175: 1731-1743. Eric Vivier is a graduate of the Ecole Nationale Vétérinaire de Maisons-Alfort and received his PhD in 5. Gauthier et al. Multifunctional Natural Killer Cell Engagers Targeting NKp46 Trigger Protective Tu- Immunology from the University of Paris XI. He completed his post-doctoral training at Harvard Medical mor Immunity. Cell, 2019, doi.org/10.1016/j.cell.2019.04.041 School, then joined Aix-Marseille University as professor at the Centre d‘Immunologie de Marseille-Lu- miny (CIML) in 1993 before becoming its director from 2008 to the end of December 2017. He is also one of the founders of Marseille-Immunopôle, an immunology cluster created in 2014 linking 5 SELESCTED REVIEWS and ESSAYS fundamental and therapeutic research, innovation and industrial development in the Aix-Marseille re- gion. 1. Vivier E. et al., Innate or adaptive immunity? The example of Natural Killer cells. Science, 2011, 331: Eric Vivier‘s work focuses on the functioning of Natural killer lymphocytes (NK) and other innate lym- 44-49. phoid cells (ILCs). Professor Vivier has published nearly 300 scientific articles and is on the list of the 2. Pradeu P. & Vivier E. The Discontinuity Theory of Immunity. Science Immunology 2016, 1, aag0479 most cited researchers (https://clarivate.com/hcr/ ). 3. Ebbo M. et al., Innate lymphoid cells: major players in inflammatory diseases. Nature Reviews Publications: total 360, h-Index: 101, > 38000 citations (See selected publications below) Immunology, 2017, 17 :665–678 http://scholar.google.fr/citations?user=NlmFOgMAAAAJ&hl=fr&oi=ao 4. Vivier E et al., Innate Lymphoid Cells: 10 years on. Cell, 2018, 174: 1054-1066. A laureate of the European Research Council (ERC advanced grants), a member of the Académie Na- 5. Chiossone L. et al., Natural killer cells and other innate lymphoid cells in cancer. Nature Reviews tionale de Médecine and the Institut Universitaire de France, Prof. Vivier has received several awards Immunology, 2018, 18: 671-688. including those from the Ligue Nationale contre le Cancer (1996, 2004 and 2013) and the European Federation of Immunological Societies (EFIS, 2004). NOTES ABSTRACT

New therapies promoting antitumor immunity have been recently developed. Most of these immuno- modulatory approaches have focused on enhancing T-cell responses, either by targeting inhibitory pathways with immune checkpoint inhibitors, or by targeting activating pathways, as with chimeric antigen receptor T cells or bispecific antibodies. Despite unprecedented successes, only a minority of cancer patients benefit from these treatments, highlighting the need to identify new cells and mole- 46 | cules that could be exploited in the next generation of immunotherapy. Given the crucial role of innate | 47 Martin Kriegel Session 5 “Suppression of translocating pathobionts in autoimmunity – an interventional paradigm for the future of immunology”

Yale School of Medicine & Roche Innovation Center 5 SELECTED PUBLICATIONS New Haven, USA 1. Vieira SM, Hiltensperger M, Kumar V, Zegarra-Ruiz D, Dehner C, Kahn N, Costa FRC, Tiniakou E, Grei- ling T, Ruff W, Barbieri A, Kriegel C, Mehta SS, Knight JR, Jain D, Goodman AL, Kriegel MA: Transloca- tion of a Gut Pathobiont Drives Autoimmunity in Mice and Humans. Science, 2018; 359:1156-1161. BIOSKETCH 2. Zegarra-Ruiz D, El Beidaq A, Iniguez, AJ, Lubrano Di Ricco M, Manfredo Vieira S, Ruff WE, Mubiru Dr. Kriegel is currently an Associate Professor Adjunct in the Department of Immunobiology at Yale D, Fine R, Sterpka J, Greiling TM, Dehner C, Kriegel MA: A diet-sensitive commensal Lactobacillus School of Medicine and a Translational Physician Scientist at Roche. His laboratory explores host-micro- strain mediates TLR7-dependent systemic autoimmunity. Cell Host Microbe, 2019; 25, 113-127. biota interactions in autoimmunity and cancer by combining human microbiome studies with gnoto- biotic models. 3. Greiling TM*, Dehner C*, Chen X*, Hughes K, Renfroe SC, Vieira SM, Ruff WE, Boccitto M, Sim S, Kriegel He had completed medical school at the Friedrich-Alexander University of Erlangen-Nuremberg, Ger- C, Chen X, Girardi M, Degnan P, Goodman AL, Wolin SL#, Kriegel MA#: Commensal Orthologs of the many, followed by postdoctoral training as an Emmy-Noether stipendee at Yale with Richard Flavell Human Autoantigen Ro60 as Triggers of Autoimmunity in Lupus. Science Translational Medicine, and at Harvard Medical School with Christophe Benoist and Diane Mathis. Dr. Kriegel has completed 2018; 10(434). pii: eaan2306. residency and rheumatology fellowship at Harvard, before returning to Yale in 2012 as a tenure-track faculty member in the Department of Immunobiology. Dr. Kriegel has received several major foundation 4. Ruff WE, Dehner C, Kim WJ, Pagovich O, Aguiar CL, Yu AT, Roth AS, Manfredo Vieira, S, Kriegel S, awards in the United States as well as national recognitions from the German Society for Endocrinology Olamide A, Mulla MJ, Abrahams VM, Kwok WW, Nussinov R, Erkan D, Goodman AL, Kriegel MA: Patho- and the German Society for Rheumatology, respectively. He holds an international patent on targeting genic beta2-glycoprotein I autoreactive T and B cells cross-react with non-orthologous mimotopes gut bacteria in immune diseases and has served as an Advisory Editor for Arthritis & Rheumatology as expressed by a common human gut commensal. Cell Host Microbe, 2019; 26: 100-113. well as a reviewer for national grant programs in the United States, United Kingdom, Switzerland and Israel. 5. Fine R, Vieira SM, Gilmore MS, Kriegel MA: Mechanisms and Consequences of Gut Commensal Trans- location in Chronic Diseases. Gut Microbes, 2019, DOI: 10.1080/19490976.2019.1629236.

ABSTRACT

Despite multiple associations between the microbiome and immune diseases, its role in autoimmunity remains poorly understood. Several mechanisms have recently been uncovered in systemic autoim- munity. These include gut commensal translocation on a cellular level and cross-reactivity as well as post-translational modification of autoantigens on a molecular level. I will focus on the concept of gut barrier leakiness and translocation of live commensals that drive autoimmune pathways in genetically predisposed hosts. The pathobiont E. gallinarum translocates to lymph nodes, liver, and spleen in an autoimmune model to induce autoantigens, endogenous retroviral antigens, Th17/Tfh cells, and auto- NOTES antibodies. An intramuscular vaccine against E. gallinarum suppresses translocation and autoimmune pathology, representing a new paradigm for pathobiont-directed therapies. Furthermore, a starch diet suppresses another translocating pathobiont, L. reuteri, that exacerbates the plasmacytoid DC-type I IFN axis in TLR7 transgenic mice. Mechanistically, diet-induced SCFAs tighten TLR7-dependent gut leakiness and suppress growth of L. reuteri in vitro and vivo. In summary, I will cover mechanisms and consequences of pathobiont translocation and outline interventions to suppress pathobionts in order to restore immune homeostasis. Modulation of immunity via the gut microbiota may be an attractive field for interdisciplinary research and the future of immunology in Berlin.

48 | | 49 Manolis Pasparakis Session 5 “The intimate connection between cell death and inflammation”

Institute for Genetics and CECAD Research Center, 5 MOST IMPORTANT PUBLICATIONS University of Cologne, Germany 1. Polykratis A, Martens A, Eren RO, Shirasaki Y, Yamagichi M, Yamaguchi Y, Uemura S, Miura M, Holz- mann B, Kollias G, Armaka M, van Loo G, Pasparakis, M. (2019) A20 prevents inflammasome-depen- dent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin binding domain. BIOSKETCH Nat. Cell Biol. 21, 731-742.

Manolis Pasparakis is interested to understand the mechanisms regulating inflammation and the pa- 2. Lin, J., Kumari, S., Kim, C., Van, T.-M., Wachsmuth, L., Polykratis, A., and Pasparakis, M. (2016). RIPK1 thogenesis of inflammatory diseases and cancer. A topic of particular interest in the Pasparakis’ lab counteracts ZBP1-mediated necroptosis to inhibit inflammation.Nature 540, 124-128. is the function of different pathways of regulated cell death, including necroptosis, pyroptosis and apoptosis, in immunity and inflammation and the underlying mechanisms. 3. Dannappel, M., Vlantis, K., Kumari, S., Polykratis, A., Kim, C., Wachsmuth, L., Eftychi, C., Lin, J., Corona, Manolis Pasparakis received his bachelor’s and Ph.D. degrees in biology from the University of Athens, T., Hermance, N., Zelic, M., Kirsch, P., Basic, M., Bleich, A., Kelliher, M., and Pasparakis, M. (2014). RIPK1 Greece. After postdoctoral training in the Institute for Genetics of the University of Cologne he started maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513, 90–94. his independent research as a group leader at the Mouse Biology Programme of EMBL in Monterotondo, Italy. He became Professor at the Institute for Genetics of the University of Cologne in 2005, where he 4. Welz, P.S., Wullaert, A., Vlantis, K., Kondylis, V., Fernandez-Majada, V., Ermolaeva, M., Kirsch, P., Ster- works since then. ner-Kock, A., van Loo, G., and Pasparakis, M. (2011). FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477, 330-334.

ABSTRACT 5. Nenci, A., Becker, C., Wullaert, A., Gareus, R., van Loo, G., Danese, S., Huth, M., Nikolaev, A., Neufert, C., Madison, B., Gumucio, D., Neurath, M.F., and Pasparakis, M. (2007). Epithelial NEMO links innate Cell death is recognized for many years as an important biological process for the maintenance of immunity to chronic intestinal inflammation.Nature 446, 557-561. tissue homeostasis as well as for pathogen defense. Until recently, cell death was synonymous to apop- tosis. However, the recent discoveries of molecularly controlled pathways of lytic cell death, such as necroptosis and pyroptosis, broadened the scope of cell death research from a predominantly apop- tosis-centric view to a wider exploration of the regulation and function of the different types of cell death. A key question that has emerged is: “why are there so many forms of cell death?” It is now generally accepted that the consequences of cell death at the level of the tissue and the organism are profoundly affected by the way a cell dies and that cell death is a central component of immunity. The currently prevailing concept is that specific types of cell death potently activate immune responses, although the underlying mechanisms remain poorly understood. A number of studies in genetic mouse models have provided experimental evidence that cell death induces inflammation in vivo, suggesting that cell death could contribute to the pathogenesis of inflammatory diseases. I will discuss our recent NOTES studies on the role of cell death in inflammation and the underlying mechanisms.

50 | | 51 Katja Simon Session 5 “Autophagy and Proteostasis in Immune Senescence”

Kennedy Institute of Rheumatology 5 SELECTED PUBLICATIONS University of Oxford 1. Puleston, D.J., H. Zhang, T.J. Powell, E. Lipina, S. Sims, I. Panse, A.S. Watson, V. Cerundolo, A.R. Town- send, P. Klenerman, and A.K. Simon, Autophagy is a critical regulator of memory CD8(+) T cell formation. Elife, 2014. 3. BIOSKETCH 2. Riffelmacher, T., A. Clarke, F.C. Richter, A. Stranks, S. Pandey, S. Danielli, P. Hublitz, Z.R. Yu, E. Johnson, As a principal investigator in Oxford, she set up an independent line of enquiry investigating autophagy T. Schwerd, J. McCullagh, H. Uhlig, S.E.W. Jacobsen, and A.K. Simon, Autophagy-Dependent Gene- in immunopoeisis. Her group discovered that autophagy, the main conserved cellular bulk degradation ration of Free Fatty Acids Is Critical for Normal Neutrophil Differentiation. Immunity, 2017. 47(3): p. pathway, maintains healthy red blood cells, stem cells and memory T cells. It promotes differentiation 466-480 and prevents ageing of immune cells. She received the 2018 Ita Askonas prize for outstanding achie- vements as a female European group leader. She is a Wellcome investigator. 3. Clarke, A.J., T. Riffelmacher, D. Braas, R.J. Cornall, and A.K. Simon, B1a B cells require autophagy for Katja Simon is Professor at Oxford University (UK) and principal investigator at the Kennedy Institute of metabolic homeostasis and self-renewal. J Exp Med, 2018. 215(2): p. 399-413. Rheumatology, studying cell fates in the hematopoietic system. She trained as an Immunologist under Avrion Mitchison, first director of the DRFZ Berlin, and found that TH1 cytokines are found in excess in 4. Clarke, A.J. and Simon, A.K. Autophagy in the renewal, differentiation and homeostasis of immune the human autoimmune disease rheumatoid arthritis (she received the EULAR Award in 1994). As a post- cells, Nature Reviews Immunology, 2018, 19 (3): p. 170-183 doc at the Centre d’Immunologie Marseille Luminy, she investigated transcription factors regulating thymic cell death. During her second postdoc in Oxford she pursued her interest in cell death molecules 5. Zhang, H., Alsaleh, G., Feltham, J., Sun, Y., Riffelmacher, T., Charles, P., Frau, L., Yu, Z., Mohammed, S., in thymic selection, inflammation and tumour immunity. Balabanov, S., Mellor, J. and Simon, A.K., Translational control of TFEB and autophagy via eIF5A rejuvenates B cell immunity. Molecular Cell, August 26, 2019

ABSTRACT

With increasing life expectancy, the number of people over 60 years is expected to double by 2050, reaching 2.1 billion worldwide. The severity of many infections increases substantially with age, and the success of childhood vaccination is widely recognized but the importance of vaccination of the elderly population is frequently underestimated. Vaccines are known to be particularly ineffective in the elder- ly, yet some vaccines such as influenza are primarily given to that age group. Immune senescence is characterized by a decline in innate and adaptive immunity together with an increase in low-grade chronic inflammation contributing to age-related diseases such as osteoarthri- tis, cardiovascular and neurodegenerative diseases. Reversing or halting immune ageing would open opportunities to improve management of age-related morbidities and have a major impact on the NOTES health of our society. The discovery of autophagy-related proteins greatly advanced the mechanistic understanding of autophagy. We showed that autophagy prevents immune aging. In this lecture, I will present our most recent data of a novel pathway relying on autophagy’s potential to improve human vaccination of the elderly. I will discuss the translational regulation of autophagy that controls proteostasis in long- lived T and B lymphocytes and novel ways to reverse immune sene- scence

52 | | 53 Thomas Blankenstein Session 6 “T-Immunology”

Institute of Immunology, 5 SELECTED PUBLICATIONS Charite, Campus Buch and Max-Delbrück Center for Molecular Medicine 1. Blankenstein T, Bonhomme F and Krawinkel U (1987). Evolution of pseudogenes in the immunoglo- bulin VH-gene family of the mouse. Immunogenetics 26: 237-248.

2. Hock H, Dorsch M, Kunzendorf U, Überla K, Qin Z, Diamantstein T and Blankenstein T (1993). BIOSKETCH Vaccinations with tumor cells genetically engineered to produce different cytokines: effectivity not superior to a classical adjuvant. Cancer Res 53: 714-716. Thomas Blankenstein works on several aspects of cancer immunology, with special focus on the de- velopment of cancer models that better resemble human cancer, the role of the tumor stroma for 3. Schüler T and Blankenstein T (2003). CD8 effector T cells reject tumors by direct antigen tumor progression and as target for immunotherapy, and the development of strategies for convenient recognition but indirect action on host cells. J Immunol 170: 4427-4431. and effective T-cell therapy. Thomas Blankenstein is research group leader at the Max Delbrück Center for Molecular Medicine (since 4. Qin Z, Schwartzkopff J, Pradera F, Kammertöns T, Seliger B, Pircher H and Blankenstein T (2003). 1993) and Director of the Institute of Immunology at the Charite in Berlin, Germany (since 2000). He A critical requirement of IFNγ-mediated angiostasis for tumor rejection by CD8 T cells. Cancer Res received his Ph.D. from the Institute of Immunology in Cologne, Germany in 1987. He joined the Institute 63: 4095-4100. of Immunology of the Free University of Berlin in 1988 and was visiting scientist in the Department of Pathology, University of Chicago, in 1991. From 2006-2018 he was spokesman of Collaborative Research 5. Qin Z and Blankenstein T (2004). A cancer immunosurveillance controversy. Nat Immunol 5: 3-4. Center (Sonderforschungsbereich TR36) on ‘Adoptive T cell therapy’.

ABSTRACT

We generated mice harboring the human gene loci encoding unrearranged TCRα and TCRβ V-(D)-J-C genes, both around 1 megabase in size. By crossing with respective mouse lines, mouse TCRα and TCRβ gene loci were inactivated, as well as mouse MHC I genes, and human MHC I gene was introduced. These mice express a diverse T cell repertoire, are not tolerant for many human tumor-associated antigens (epitopes) and allow isolation of human TCR, which do not exist in the human repertoire or only at exceedingly low frequencies. They proved useful to isolate human TCRs of higher functional activity compared to those isolated from humans.

NOTES

54 | | 55 Gerald Willimsky Session 6 “Oncogene-specific T cells at work: in experimental models and in translation”

Experimental and Translational Cancer Immunology In the course of analyzing the human mutanome-encoded repertoire of tumor-specific T cell epitopes Institute of Immunology (Charité - Universitätsmedizin Berlin) through the isolation of neoantigen-specific T cell receptors (TCRs) we identified a number of immuno- and German Cancer Research Center (DKFZ Heidelberg) genic neoepitopes derived from recurrent activating mutations. Currently, their potential for proof of concept clinical testing, e.g. utilizing TCRs targeting mutations in the GTPases of the Rac family, is analyzed. BIOSKETCH

Cancer cells can be recognized by T cells, the success story of checkpoint inhibitors has reinforced this 5 SELECTED PUBLICATIONS notion. To study the spontaneous and therapy-induced immune response against non-transplanted cancers mice with conditional oncogene-driven cancer development have been analyzed. In order to 1. Hoser D, Schön C, Loddenkemper C, Lohneis P, Kühl AA, Sommermann T, Blankenstein T, Willimsky G. test the efficiency of T cell receptor (TCR) gene-modified T cells in vivo in a clinically relevant context 2018. Oncogene-specific T cells fail to eradicate lymphoma-initiating B cells in mice. Blood 132: 924. these autochthonous cancer models are further developed with therapeutically relevant cancer-speci- fic antigens, e.g. using in vivo CRISPR/Cas system. This also includes the identification of relevant hu- 2. Schmidt K, Keller C, Kühl AA, Textor A, Seifert U, Blankenstein T, Willimsky* G, Kloetzel* PM. 2018. man immunogenic cancer rejection antigens as well as generation of human TCRs with optimal affinity. ERAP1-dependent antigen cross-presentation determines efficacy of adoptive T-cell therapy in Suitable TCRs will be pursued into clinical application, accompanied with exploration of the feasibility mice. Cancer Res 78: 3243. *Contributed equally. of non-viral CRISPR T cell engineering. 3. Schmidt K, Zilio S, Schmollinger JC, Bronte V, Blankenstein T, and Willimsky G. 2013. Differently since 2016 Joint DKTK-Professorship for Experimental and Translational Cancer immunogenic cancers in mice induce immature myeloid cells that suppress CTL in vitro but not in Immunology, Charité - Universitätsmedizin Berlin and German Cancer vivo following transfer. Blood 121:1740. Research Center, Heidelberg 2000-2015 Research Group Leader at Charité - Universitätsmedizin Berlin, 4. Willimsky G, Schmidt K, Loddenkemper C, Gellermann J, and Blankenstein T. 2013. Virus-induced Institute of Immunology hepatocellular carcinomas cause antigen-specific local tolerance.J Clin Invest 123: 1032. 1996-2000 Staff Scientist at the Max-Delbrück-Center of Molecular Medicine, Berlin 1994-1996 Postdoctoral Scientist at the Max-Delbrück-Center of Molecular Medicine, 5. Willimsky, G, Blankenstein T. 2005. Sporadic immunogenic tumours avoid destruction by inducing Berlin T-cell tolerance. Nature 437:141. 1994-1996 Postdoctoral Scientist at ´Institut für Genbiologische Forschung´, Berlin 1985-1993 Studies of Chemistry/Biochemistry; Technical University Berlin, Philipps-University Marburg, PhD-Thesis 1993

ABSTRACT NOTES To this end sporadic and virus-induced cancer development using conditional oncogene (SV40 large T-antigen, TAg) expression have shown profound cancer-induced systemic tolerance already at the premalignant stage of sporadic cancers on the one hand and induction of systemic immunity but local antigen specific cytotoxic T cell (CTL) tolerance in virus-induced cancers on the other hand. To analyze the interaction between (pre-)malignant B cells and T cells, we generated transgenic mice that allow B cell-specific TAg induction. Constitutive TAg expression in CD19+ cells resulted in TAg-tolerant CD8+ T cells early in life and development of B cell lymphomas. In contrast, when TAg was induced in B cells of adult mice that had retained TAg-competent CD8+ T cells, lymphoma formation was exceptionally rare late in life. Here, increased lymphoma incidence in the absence of TAg-specific T cells suggested T 56 | cell-mediated inhibition of lymphoma progression. | 57 Andrea Schietinger Session 6 “Molecular and epigenetic programs defining tumor-specific T cell differentiation”

Andrea Schietinger, PhD 5 SELECTED PUBLICATIONS Immunology Program | Memorial Sloan Kettering Cancer Center New York, USA 1. Scott AC, Dündar F, Zumbo P, Chandran SS, Klebanoff CA, Shakiba M, Trivedi P, Menocal L, Appleby H, Camara S, Zamarin D, Walther T, Snyder A, Femia MR, Comen EA, Wen HY, Hellmann MD, Anandasabapathy N, Liu Y, Altorki NK, Lauer P, Levy O, Glickman MS, Kaye J, BIOSKETCH Betel D, Philip M, Schietinger A. “TOX is a critical regulator of tumour-specific T cell differentiation.” Dr. Andrea Schietinger is an Assistant Member in the Immunology Program at Memorial Sloan Kettering Nature 2019; 571(7764):270-274. Cancer Center (MSKCC), and Assistant Professor at Weill Cornell Medical College in New York since 2015. Her laboratory studies the molecular and epigenetic mechanisms underlying T cell differentiation and 2. Philip M, Fairchild L, Sun L, Horste E, Camara S, Shakiba M, Scott AC, Viale A, Lauer P, Merghoub T, dysfunction in the context of self-tolerance, autoimmunity and tumors (Nature 2017; Nature 2019). Hellmann M, Wolchok JD, Leslie CL, Schietinger A. “Discrete chromatin states define tumor-specific T cell dysfunction and therapeutic reprogramma- After receiving her degree in Pharmacology from the University of Hamburg in 2001, she enrolled in bility.” a joint PhD program between the Ludwig Maximilian University of Munich (LMU) and The University Nature 2017; 545(7655):452-456. of Chicago (UofC). During her PhD she worked in Dr. Hans Schreiber’s laboratory at the UofC, where she studied how aberrant posttranslational glycosylation of wildtype proteins in cancer cells creates 3. Schietinger A, Philip M, Krisnawan VE, Chiu EY, Delrow JJ, Basom RS, Lauer P, Brockstedt DG, Knob- tumor-specific neo-antigens (Science, 2006); she received her PhD in 2007 from the LMU. As a postdoc- laugh SE, Hämmerling GJ, Schell TD, Garbi N, Greenberg PD. “Tumor-specific T cell dysfunction is a toral fellow in Dr. Philip Greenberg’s lab at the University of Washington in Seattle, she investigated the dynamic antigen-driven differentiation program initiated early during tumorigenesis.” transcriptional programs needed for self-reactive T cells to maintain peripheral self-tolerance (Science, Immunity 2016; 45(2):389-401. 2012). Dr. Schietinger is the recipient of numerous awards and grants, including the NIH Director‘s New Innovator Award in 2017, and the Lloyd Old STAR Award from the Cancer Research Institute in 2019. 4. Schietinger A, Delrow J, Basom R, Blattman JN, Greenberg PD. “Rescued tolerant CD8 T cells are preprogrammed to reestablish the tolerant state.” Science 2012; 335(6069): 723-7. ABSTRACT 5. Schietinger A, Philip M, Yoshida BA, Azadi P, Liu H, Meredith SC, Schreiber H. T cell responses to cancers differ depending on the nature of the target antigen: tumor antigens that “A mutant chaperone converts a wild-type protein into a tumor-specific antigen.” are self-proteins are generally weakly immunogenic due to pre-existing self-tolerance, whereas tumor Science 2006; 314(5797): 304-308. antigens that are tumor-specific (e.g. mutated proteins) are potentially highly immunogenic because the immune system has not been exposed to these antigens. We recently demonstrated that tumor-spe- cific T cells differentiate to a non-responsive state following initial encounter with tumor antigen, even before the emergence of a pathologically-defined tumor. While this state is initially reversible, it pro- gresses to a fixed state that cannot be rescued, and the reversible and fixed non-responsive states NOTES were defined by discrete chromatin states. This pathway resembles what we observe in peripheral self-tolerance in which self-reactive T cells differentiate to an epigenetically-encoded tolerant state after encountering self-antigen. Thus, the ad- aptive immune system is under strong pressure to permanently neutralize self-reactive T cells through a specific, epigenetically-enforced differentiation program, and while this differentiation pathway ef- fectively prevents autoimmunity for the most part, unfortunately, it just as effectively subverts tu- mor-specific anti-cancer responses. New insights into the epigenetic and molecular programs under- lying hyporesponsiveness in tumor-specific T cells will be discussed.

58 | | 59 Mathias Heikenwälder Session 6 “On the role of immune cells on NASH/liver cancer and its consequences for therapy”

Department Chronic Inflammation and Cancer, 5 SELECTED PUBLICATIONS German Cancer research center (DKFZ), Heidelberg, Germany. 1. O’Connor T, Zhou X, Kosla J, Adili A, Garcia-Beccaria M, Kotsiliti E, Pfister D, Johlke AL, Sinha A, San- kowski R, Schick M, Lewis R, Dokalis N, Seubert B, Höchst B, Inverso D, Heide D, Zhang W, Weihrich P, Manske K, Wohlleber D, Anton M, Höllein A, Seleznik G, Bremer J, Bleul S, Augustin H, Scherer F, BIOSKETCH Ködel U, Weber A, Protzer U, Förster R, Wirth T, Aguzzi A, Meissner F, Prinz M, Baumann B, Höpken UE, Knolle P, von Baumgarten L, Keller U, Heikenwalder M. “Age-related gliosis promotes central Since October 2015 I am heading the department “Chronic Inflammation and Cancer” at the German nervous system lymphoma metastasis through CCL19-mediated tumor cell retention”. Cancer Research Center (DKFZ). My laboratory aims at investigating chronic inflammatory diseases Cancer Cell. 2019 Sep; 36, 1-18 September 16, 2019. driving tissue-damage (e.g. dietary-, virally-induced), autoimmunity and cancer, with focus on hepato- biliary/gastrointestinal diseases. We aim at understanding the systemic effects of pathologies and the 2. Malehmir M, Pfister D, Gallage S, Szydlowska M, Inverso D, Kotsiliti E, Leone V, Peiseler M, Surewaard interplay between non-lymphoid tissues, the hepatobiliary tract and the immune system (e.g. liver-gut BGJ, Rath D, Ali A, Wolf MJ, Drescher H, Healy ME, Dauch D, Kroy D, Krenkel O, Kohlhepp M, Engleitner axis). We focus on functional, comparative studies using human patient-derived tissue, animal models T, Olkus A, Sijmonsma T, Volz J, Deppermann C, Stegner D, Helbling P, Nombela-Arrieta C, Rafiei A, and perform pre-clincial/clinical trials. Hinterleitner M, Rall M, Baku F, Borst O, Wilson CL, Leslie J, O‘Connor T, Weston CJ, Adams DH, Sheriff After my studies of genetics/microbiology at the Max-Perutz laboratories (MPL)/institute of molecular L, Teijeiro A, Prinz M, Bogeska R, Anstee N, Bongers MN, Notohamiprodjo M, Geisler T, Withers DJ, pathology (IMP), Vienna, I completed my master at the Max-Delbrück Center (MDC), Berlin. Thereafter, Ware J, Mann DA, Augustin HG, Vegiopoulos A, Milsom MD, Rose AJ, Lalor PF, Llovet JM, Pinyol R, I performed my Ph.D. at the University Hospital Zurich (USZ; institute of neuropathology) in the field Tacke F, Rad R, Matter M, Djouder N, Kubes P, Knolle PA, Unger K, Zender L, Nieswandt B, Gawaz M, of neuroinflammation/neurodegeneration. After 2 years post-doc with own funding at the department Gawaz M, Weber A. and Heikenwalder M. „Platelet GPIba is a mediator and potential interventional of pathology, USZ, I became Prof. Max-Cloëtta-fellow and independent PI, focusing on inflammation-in- target for NASH and subsequent liver cancer.” duced tissue damage. After my habilitation at the medical faculty, USZ, I became a Hofschneider Pro- Nature Medicine. 2019 Apr;25(4):641-655. doi: 10.1038/s41591-019-0379-5. Epub 2019 Apr 1. fessor (W2)/Helmholtz Young Group Investigator (HYGI) at the institute of virology, Klinikum Rechts der Isar (MRI)/Helmholtz Zentrum für Gesundheit und Umwelt (HMGU), Munich, focusing on the link between 3. Yuan D, Huang S, Berger E, Liu L, Gross N, Heinzmann F, Ringelhan M, Connor TO, Stadler M, Meister M, chronic inflammation, tissue damage, autoimmunity and cancer in 2010. Weber J, Öllinger R, Simonavicius N, Reisinger F, Hartmann D, Meyer R, Reich M, Seehawer M, Leone V, Höchst B, Wohlleber D, Jörs S, Prinz M, Spalding D, Protzer U, Luedde T, Terracciano L, Matter M, Longerich T, Knolle P, Ried T, Keitel V, Geisler F, Unger K, Cinnamon E, Pikarsky E, Hüser N, Davis RJ, ABSTRACT Tschaharganeh DF, Rad R, Weber A, Zender L, Haller D, Heikenwalder M. “Kupffer-cell derived TNF triggers cholangiocellular tumorigenesis through JNK due to chronic mitochondrial dysfunction Chronic hepatitis is the main driver of liver-cancer, the third most common cause for cancer-related and ROS”. death in humans. Different etiologies cause chronic hepatitis and cancer: Chronic viral infections with Cancer Cell. 2017, 31:771-789. Hepatitis B or C viruses (HBV, HCV), chronic alcohol abuse or chronic high-caloric diet in combination with sedentary life-style. Due to consumption of high-caloric food combined with increased sedentary 4. Wolf MJ, Adili A, Piotrowitz K, Abdullah Z, Boege Y, Stemmer K, Ringelhan M, Simonavicius N, Egger M, life-style, overweight, metabolic syndrome and obesity incidence has grown rapidly in Western (e.g. Wohlleber D, Lorentzen A, Einer C, Schulz S, Clavel T, Protzer U, Thiele C, Zischka H, Moch H, Tschöp USA) but also in developing countries (e.g. India), affecting adults and children. Although chronic viral M, Tumanov AV, Haller D, Unger K, Karin M, Kopf M, Knolle P, Weber A°, Heikenwalder M°. “Metabolic infections are still the leading cause for liver-cancer, alcoholic steatohepatitis (ASH), non-alcoholic activation of intrahepatic CD8+ T-cells and NKT-cells causes nonalcoholic steatohepatitis and hepa- fatty liver (NAFL) and subsequent non-alcoholic steatohepatitis (NASH) have become important etiolo- tocellular carcinoma via cross-talk with hepatocytes”. gies for liver-cancer. We have generated several pre-clinical mouse models to study the mechanisms of Cancer Cell. 2014, 26:549-564. inflammation-induced liver-cancer in the context of a metabolic syndrome. These models recapitulate several human pathophysiological hallmarks of NASH/ASH induced liver-cancer. Adaptive but also in- 5. Wolf MJ, Hoos A, Bauer J, Boettcher S, Knust M, Weber A, Simonavicius N, Schneider C, Lang M, Stürzl nate immune cells play an important role in driving NASH and subsequent HCC and - at the same time M, Croner RS, Konrad A, Manz MG, Moch H, Aguzzi A, van Loo G, Pasparakis M, Prinz M, Borsig L, Hei- - contribute to tumor surveillance efficacy. kenwalder M. “Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation Here, I will report on the interplay between different types of immune cells driving NASH and liver-can- via the JAK2-Stat5 and p38MAPK pathway”. 60 | cer and how this affects anti-tumor therapy strategies. Cancer Cell. 2012, 22:91-105. | 61 Florian Greten Session 6 “The inflammatory tumor microenvironment”

1Institute for Tumor Biology and Experimental Therapy, Georg-Speyer- 5 MOST IMPORTANT PUBLICATIONS Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt am Main 2Frankfurt Cancer Institute, Goethe University Frankfurt 1. Greten, FR, Grivennikov, SI: Inflammation and Cancer: Triggers, Mechanisms and Consequences. Immunity. 2019 Jul 16;51(1):27-41

BIOSKETCH 2. Ziegler, PK, Bollrath, J, Pallangyo, CK, Matsutani, T, Canli, Ö, DeOliveira, T, Diamanti, MA, Müller, N, Gamrekelashvili, Putoczki, T, Horst, D, Mankan, AK, Öner, MG, Müller, S, Müller-Höcker, J, Kirchner, T, Florian R. Greten is Chair of Tumor Biology at the Goethe University Frankfurt and Director of Institute of Slotta-Huspenina, J, Taketo, MM, Reinheckel, T, Dröse, S, Larner, AC, Wels, WS, Ernst, M, Greten, TF, Tumor Biology and Experimental Therapy, Georg-Speyer-Haus since August 2013. He is a founder of the Arkan, MC, Korn, T, Wirth, D, Greten, FR.: Mitophagy in intestinal epithelial cells triggers adaptive newly established Frankfurt Cancer Institute (FCI) and acts as Speaker of the LOEWE-Center Frankfurt immunity during tumorgenesis. Cell. 2018 Jun 28;174(1):88-101 Cancer Institute since 01/2019. From 2010-2013 he was Professor of Molecular Gastrointestinal Oncology (W2) at the Klinikum rechts der Isar, Technical University Munich and prior to that Emmy-Noether Group 3. Varga, J., Greten FR.: Cell Plasticity in Epithelial Homeostasis and Tumorigenesis. Nat Cell Biol. Leader and Resident in Internal Medicine, Dept. of Gastroenterology at the Klinikum rechts der Isar, 2017, 19:1133-1141 Technical University Munich. From 2001-2004 he performed his Post-Doctoral Studies with Michael Karin at the University of California, San Diego. He started his internship in Internal Medicine in 1998 at the 4. Canli Ö, Adele M Nicolas, Gupta J, Finkelmeier F, Olga Goncharova, Pesic M, Tobias Neumann, Horst Dept. of Medicine, University of Ulm after completing his Medical Studies at the University of Hamburg D, Löwer M, Sahin U, Greten FR. Myeloid cell-derived reactive oxygen species induce epithelial and Vienna. Currently, he acts as speaker of the DFG Research Unit 2438 ‘Cell Plasticity in Colorectal mutagenesis. Cancer Cell, 2017, 32:869-883. Carcinogenesis’, Deputy Head of the Board of Trustees of the Paul Ehrlich Foundation, member of the DFG committee ‘Hinterzartener Kreis für Krebsforschung’ and since 2019 he is the Head of the Grants 5. Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Göktuna SI, Ziegler PK, Canli O, Hejimans J, Committee “Clinical and Basic Research” of the Deutsche Krebshilfe (German Cancer Aid). Huels DJ, Moreaux G, Rupec RA, Gerhard M, Schmid R, Barker N, Clevers H, Lang R, Neumann, J, Kirch- ner T, Taketo MM, van den Brink GR, Sansom OJ, Arkan MC, and Greten FR. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell like properties. Cell 2013; 152:25-38. ABSTRACT

The tumor microenvironment is composed of different cells that can be grouped into three classes: cancer-associated fibroblasts, vascular cells and infiltrating immune cells. The relative abundance of these respective cell types as well as their polarization profile can greatly vary and often predicts pro- gnosis and response to therapy. Cells of all three groups can control tumor cell proliferation, cell death, growth suppressor evasion, energy metabolism, angiogenesis, immune evasion as well as invasion in a non-autonomous manner. Thus, it has become unequivocally evident that tumor development depends on the intricate reciprocal interplay of mutagenized tumor cells with their local and distant microen- vironment. Cytokines and other signal proteins control the plasticity of stromal, tumor and cancer NOTES stem like cells in an autocrine and paracrine manner thereby shaping the complex cellular contexture, which ultimately forms a pro- or anti-tumorigenic milieu. A detailed understanding of the cellular and molecular mechanisms underlying these complex interactions of tumor, stroma and immune cells may help to identify novel therapeutic targets. We recently identified signaling pathways during early and late tumorigenesis that highlight the importance of tumor cells for T cell polarization and suppression of adaptive immunity and that help to understand why stroma-rich colon tumors may be associated with a worse prognosis.

62 | | 63 Norbert Suttorp Session 7 “Host directed approaches to diagnostics, treatment and prevention of infectious diseases” part I

Department of Infectious Diseases and Respiratory Medicine, 5 SELECTED PUBLICATIONS Charité - Universitätsmedizin Berlin 1. Maschirow L, Suttorp N, Opitz B. Microbiota-Dependent Regulation of Antimicrobial Immunity in the Lung. Am J Respir Cell Mol Biol. 2019; 61:284-289.

BIOSKETCH 2. Robak OH, Heimesaat MM, Kruglov AA, Prepens S, Ninnemann J, Gutbier B, Reppe K, Hochrein H, Su- ter M, Kirschning CJ, Marathe V, Buer J, Hornef MW, Schnare M, Schneider P, Witzenrath M, Bereswill • Study of medicine in Münster an Giessen. Post-doc-time at Stanford university and university S, Steinhoff U, Suttorp N, Sander LE, Chaput C, Opitz B. Antibiotic treatment-induced secondary IgA of Giessen. deficiency enhances susceptibility to Pseudomonas aeruginosa pneumonia. J Clin Invest. 2018; 128:3535-3545. • Full C4-Professor, Chairman and Director, Dept. of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité, Berlin (since 1999). 3. Rabes A, Suttorp N, Opitz B. Inflammasomes in Pneumococcal Infection: Innate Immune Sensing and Bacterial Evasion Strategies. Curr Top Microbiol Immunol. 2016; 397:215-27. • Speaker of DFG-funded collaborative research center (CRC) SFB/TR-84 (innate immunity of the lung) (since 2010) 4. Tabeling C, Yu H, Wang L, Ranke H, Goldenberg NM, Zabini D, Noe E, Krauszman A, Gutbier B, Yin J, Schaefer M, Arenz C, Hocke AC, Suttorp N, Proia RL, Witzenrath M, Kuebler WM. CFTR and sphingoli- • Speaker of BMBF-funded PROGRESS (susceptibility to infection) (since 2007) pids mediate hypoxic pulmonary vasoconstriction. Proc Natl Acad Sci U S A. 2015;112:E1614-23. doi: 10.1073/pnas.1421190112. • Member of Advisory Board of the German Medical Association (since 2003) 5. Fiedler U, Reiss Y, Scharpfenecker M, Grunow V, Koidl S, Thurston G, Gale NW, Witzenrath M, Rosseau • Speaker of BMBF-funded competence network CAPNETZ (com. acq.pneumonia) (2002-2012). S, Suttorp N, Sobke A, Herrmann M, Preissner KT, Vajkoczy P, Augustin HG: Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med. • Member of the German National Academy of Science-Leopoldina (since 2000) 2006, 12(2):

ABSTRACT

My major interest relates to innate immunity of the lung in the context of infection, inflammation, resolution and repair of lung tissue. Hereby we focus on macrophage- and PMN-biology. Mechanisms of endothelial lung barrier failure are a further focus of our work. The intention is to apply host directed therapies to improve pneumonia outcome and to design therapies that go beyond antibiotics. In a more clinical approach we identified new biomarkers for disease severity using genotyping, tran- NOTES scriptomics and proteomics in well characterized patient cohorts with pneumonia. Finally we apply methods of system medicine in pneumonia to model an infection of the lung tissue (CAPSyS-project).

64 | | 65 Leif-Erik Sander Session 7 “Host directed approaches to diagnostics, treatment and prevention of infectious diseases” part II

Department of Infectious Diseases and Respiratory Medicine 5 SELECTED PUBLICATIONS Charité – Universitätsmedizin Berlin 1. Georg P, Sander LE. Innate sensors that control vaccine responses. Curr Opin Immunol 2019;59:31- 41

BIOSKETCH 2. Ugolini M*, Gerhard J*, Burkert S*, Jensen KJ, Georg P, Ebner F, Volkers S, Thada S, Dietert K, Bauer L, Schäfer A, Helbig ET, Opitz B, Kurth F, Sur S, Dittrich N, Gaddam S, Conrad ML, Benn CS, Blohm U, Leif Erik Sander is a clinician scientist specializing in internal medicine, pulmonology and infectious Gruber AD, Hutloff A, Hartmann S, Boekschoten MV, Müller M, Jungersen G, Schumann RR, Suttorp N, diseases. His research is focused on dissecting mechanisms of infection and vaccination, and on the Sander LE. Recognition of microbial viability via TLR8 promotes T follicular helper cell differentia- development of novel immunization strategies against the growing threat of multi-drug resistant in- tion and vaccine responses. Nat Immunol 2018;19:386-96 fections. His work has revealed an inherent capacity of the immune system to detect microbial viability, which appears to be a central driver in immunity to infections and vaccination. 3. Garaude J, Acín-Pérez R, Martínez-Cano S, Enamorado M, Ugolini M, Nistal-Villán E, Hervás-Stubbs A graduate of the Hannover Medical School, he defended his dissertation in 2006. Following his clinical S, Pelegrín P, Sander LE, Enríquez JA, Sancho D. Mitochondrial respiratory-chain adaptations in residency in the Dept. of Medicine at the University Hospital Aachen, he received a DFG fellowship to macrophages contribute to antibacterial host defense. Nat Immunol 2016;17:1037-1045 perform his postdoctoral training in the laboratory of Julie Blander at the Mount Sinai School of Me- dicine in New York, NY in 2008. In 2012, he was accepted to the Emmy Noether Program of the DFG and 4. Sander LE, Davis MJ, Boekschoten MV, Amsen D, Dascher CC, Ryffel B, Swanson JA, Müller M, Blander established his research group at the Dept. of Infectious Diseases and Respiratory Medicine at Charité. JM. Detection of prokaryotic mRNA signifi es microbial viability and promotes immunity.Nature 2011 He has received several awards, including the ‘Theodor Frerichs Preis’ of the German Society of Inter- 474:385-9 nal Medicine (DGIM). He is a clinical consultant, and in 2016, he was named W2 Professor of Infectious Diseases, Immunology and Vaccinology at Charité. 5. Sander LE, Sackett SD, Dierssen U, Beraza N, Linke RP, Müller M, Blander JM, Tacke F, Trautwein C: Hepatic Acute Phase Proteins Control Innate Immune Responses During Infection by Promoting Myeloid Derived Suppressor Cell Function. J Exp Med 2010; 207(7):1453-64 ABSTRACT

Vaccines represent arguably one of the most effective public health interventions of all times. Des- pite the long-standing success, many principles of vaccination remain incompletely understood. For instance, the widely-observed qualitative difference in the immune responses to live and non-live vaccines is still largely unexplained. Live attenuated vaccines (LAVs) often induce life-long protective immunity following a single immunization, which is rarely achieved with non-live vaccine preparations. By virtue of their microbial origin, LAVs contain natural ligands (PAMPs) and exert inherent adjuvant activity. We have previously demonstrated that antigen presenting cells (APCs) distinguish live from inanimate microbial matter via recognition of conserved viability-associated molecular signals, so-cal- NOTES led ‘vita-PAMPs’. We have identifi ed the detection of microbial viability by APCs as a potent driver of T follicular helper cell differentiation and vaccine responses in humans and pigs. Yet, despite the apparent relevance of innate immune signals in vaccine responses, relatively little is known about the interaction of common LAVs, like the measles vaccine, with the innate immune system. I will present recent insights into the human immune response to LAVs and I will discuss our vision of developing vaccines that combine the unrivalled effi cacy of LAVs with the superior safety profi le and convenience of modern subunit vaccines.

66 | | 67 Susanne Herold Session 7 “Macrophages – key effector cells in organ damage and injury resolution in the infected lung”

Universities of Giessen & Marburg Lung Center, German Center for Lung and BMDM-expressed effector molecules which seem to be directly involved in epithelial regeneration Research (DZL), Excellence Cluster Cardio-Pulmonary Institute orchestrated within distinct stem cell niches of the lung in the later stage of infection. Ultimately, such Department of Medicine II | Klinikstr. 33, 35390 Giessen, Germany effector molecules when therapeutically applied to pneumonic mice substantially increased their sur- vival, highlighting the putative translational relevance of these findings.

BIOSKETCH 5 SELECTED PUBLICATIONS My research addresses the molecular mechanisms of phagocyte-epithelial cell interactions during pa- thogen-induced lung injury regarding host defense, epithelial barrier function, and stem cell niche-me- 1. Peteranderl C, Morales-Nebreda L, Selvakumar B, Lecuona E, Schmoldt C, Bespalowa J, Vadasz I, diated tissue regeneration, with a focus on influenza virus and bacterial pneumonia. My projects aim at Morty RE, Wolff T, Pleschka S, Gattenloehner S, Fink L, Mayer K, Lohmeyer J, Seeger W, Sznajder JI, defining novel therapeutic targets for treatment to attenuate lung injury and to foster organ regenera- Mutlu GM, Budinger GRS, Herold S. Macrophage-epithelial paracrine crosstalk inhibits lung edema tion in severe lung infection in a translational bench-to-bedside approach. clearance during influenza infection.J Clin Invest 126(4):1566-80, 2016. I received an MD title (Dr. med.) in 2003 and followed a clinician-scientist career path as member of the International Graduate Program “Molecular Biology and Medicine of the Lung” where I graduated with 2. Herold S, Hoegner K, Vadász I, Gessler T, Wilhelm J, Mayer K, Morty RE, Walmrath HD, Seeger W, a PhD title in 2008 at the Justus-Liebig University. I got board-certified in Internal Medicine, Infectious Lohmeyer J. Inhaled GM-CSF as treatment of pneumonia-associated acute respiratory distress syn- Diseases and Pulmonary Medicine. Since 2013 I am an Adjunct Professor at Northwestern University, drome. Am J Respir Crit Care Med. 189(5):609-11, 2014. Feinberg School of Medicine (Division of Pulmonary and Critical Care Medicine), became DZL W2 Pro- fessor for Acute Lung Injury at the JLU Giessen in 2015, and W3 Professor for Pulmonary Infections in 3. Unkel B, Hoegner K, Clausen BE, Lewe-Schlosser P, Bodner J, Gattenloehner S, Seeger W, Lohmeyer J, 2018, the latter associated with the Coordinator Position of the DFG-funded Clinical Research Unit 309 Herold S. Alveolar epithelial cells orchestrate dendritic cell functions by release of granulocyte-ma- “Virus-induced Lung Injury” (KFO309) and the Clinical Section Chair for Infectious Diseases at the De- cophage colony stimulating factor in influenza virus pneumonia. J Clin Invest 122(10):3652-64, partment of Medicine II. I am currently the Co-Speaker of the Berlin-Giessen SFB TR84 “Innate Immunity 2012. of the Lung” and Steering Member of the DFG-funded Clinician-Scientist Program “JLU-CAREER”. 4. Herold S, Shafiei Tabar T, Janßen H, Högner, K, Cabanski M, Lewe-Schlosser P, Albrecht J, Driever F, Vadasz I, Seeger W, Steinmüller M, Lohmeyer J. Exudate macrophages attenuate epithelial injury by ABSTRACT the release of IL-1 receptor antagonist in gram-negative pneumonia. Am J Respir Crit Care Med 183:1380-1390, 2011. Lung macrophages are a heterogeneous cell population well-known to set up the first line of defen- se against invading pathogens, but also increasingly recognized to be involved in lung homeostatic 5. Herold S, Steinmueller M, von Wulffen W, Cakarova L, Pinto R, Pleschka S, Mack M, Kuziel WA, Seeger and regenerative processes based on their functional plasticity. Tissue-resident alveolar macrophages W, Lohmeyer J. Lung epithelial apoptosis in influenza virus pneumonia: The role of macrophage (TR-AM) derive from yolk-sac progenitors, seed the organ early during embryogenesis and self-renew TNF-related apoptosis-inducing ligand. J Exp Med 205(13):3065-77, 2008. locally during homeostasis in presence of GM-CSF, which also significantly increases their host defense capacity. In contrast, their circulating counterparts, bone marrow-derived (inflammatory) macropha- ges (BMDM), are readily recruited to the site of infection or injury and gradually replace the TR-AM niche when depleted during infection, but might also cause substantial epithelial injury via release of NOTES pro-apoptotic factors like TRAIL. The spatiotemporal appearance of BMDM in the lung upon an infectious insult occurs in a highly coor- dinated manner. BMDM are subjected to extensive transcriptional and metabolic reprogramming by al- veolar microenvironmental signals that shape their fate and function, i.e. their anti-pathogen defense potential versus their tissue-protective/regenerative profile and their capacity to replenish the TR-AM niche. Transcriptome profiling combined with functional analyses using organoid modeling and adop- tive intrapulmonary transfer of highly purified BMDM phenotypes confirmed that BMDM have diverse 68 | gene expression profiles associated with defined functional phenotypes. We identified key programs | 69 Florian Klein Session 7 “Broadly Neutralizing Antibodies for HIV-1 Immunotherapy”

Institute of Virology, University of Cologne Fürst-Pückler-Str. 56 5 SELECTED PUBLICATIONS 50935 Cologne, Germany 1. Ehrhardt SA*, Zehner M*, Krähling V, Cohen-Dvashi H, Kreer C, Elad N, Gruell H, Ercanoglu MS, Schommers P, Gieselmann L, Eggeling R, Dahlke C, Wolf T, Pfeifer N, Addo MM, Diskin R, Becker S, Klein F. Polyclonal and convergent antibody response to Ebola virus vaccine rVSV-ZEBOV. Nat Med BIOSKETCH (2019)

Florian Klein is professor and director of the Institute of Virology at the University of Cologne. His rese- 2. Mendoza P*, Gruell H*, Nogueira L, Pai JA, Butler AL, Millard K, Lehmann C, Suárez I, Oliveira TY, arch focuses on the development of human B lymphocytes and antibodies, with a particular interest in Lorenzi JCC, Cohen YZ, Wyen C, Kümmerle T, Karagounis T, Lu CL, Handl L, Unson-O‘Brien C, Patel R, the humoral immune response to HIV-1 and other viral pathogens. Together with his team, he employs Ruping C, Schlotz M, Witmer-Pack M, Shimeliovich I, Kremer G, Thomas E, Seaton KE, Horowitz J, West new approaches for single B cell analyses and humanized mouse models. In addition, his team conducts AP Jr, Bjorkman PJ, Tomaras GD, Gulick RM, Pfeifer N, Fätkenheuer G, Seaman MS, Klein F*, Caskey early-phase clinical trials to translate basic laboratory findings into clinical applications. M*, Nussenzweig MC*. Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature. (2018) Florian Klein received his MD degree from Cologne University in 2005 following clinical training in inter- nal medicine. In 2009, he joined the Laboratory of Molecular Immunology at the Rockefeller University, 3. Caskey M.*, Schoofs T.*, Gruell H.*, Settler A., Karagounis T., Kreider E.F., Murrell B., Pfeifer N., No- where he became Instructor in Clinical Investigation in 2011, Chief Clinical Scholar in 2012, and Assistant gueira L., Oliveira T.Y., Learn G.H., Cohen Y.Z., Lehmann C., Gillor D., Shimeliovich I., Unson-O’Brien Professor in 2013. In 2015, Dr. Klein took up a DFG-Heisenberg-Professorship at the University of Cologne C., Weiland D., Robles A., Kümmerle T., Wyen C., Levin R., Witmer-Pack M., Eren K., Ignacio C., Kiss and became professor in Virology in 2017. S., West A.P., Mouquet H., Zingman B.S., Gulick R.M., Keler T., Bjorkman P.J., Seaman M.S., Hahn B.H., Fätkenheuer G., Schlesinger S.J., Nussenzweig M.C.*, Klein F.*, Antibody 10-1074 suppresses viremia in HIV-1-infected individuals. Nat Med. (2017) ABSTRACT 4. Klein, F.*, Diskin, R.*, Scheid, J.F., Gaebler, C., Mouquet, H., Georgiev, I.S., Pancera, M., Zhou, T., Incesu, Broadly neutralizing antibodies (bNAbs) targeting HIV-1 can prevent infection in animal models and are R.B., Fu, B.Z., Gnanapragasam, P.N., Oliveira, T.Y., Seaman, M.S., Kwong, P.D., Bjorkman, P.J., and Nus- under investigation for passive immunization in clinical trials. Moreover, bNAbs have been demons- senzweig, M.C., Somatic mutations of the immunoglobulin framework are generally required for trated to suppress viremia in HIV-1-infected individuals. While these results highlight the significant broad and potent HIV-1 neutralization. Cell. (2013) clinical potential of bNAbs, pre-existing and de novo HIV-1 resistance causes treatment failure and limits bNAb applications in humans. Strategies to overcome viral escape and to enhance the efficacy of bNAbs 5. Klein, F., Halper-Stromberg, A., Horwitz, J.A., Gruell, H., Scheid, J.F., Bournazos, S., Mouquet, H., Spatz, are therefore critical. We will discuss current approaches to successfully implement antibody-mediated L.A., Diskin, R., Abadir, A., Zang, T., Dorner, M., Billerbeck, E., Labitt, R.N., Gaebler, C., Marcovecchio, therapy in HIV-1 infection. P.M., Incesu, R.B., Eisenreich, T.R., Bieniasz, P.D., Seaman, M.S., Bjorkman, P.J., Ravetch, J.V., Ploss, A., and Nussenzweig, M.C., HIV therapy by a combination of broadly neutralizing antibodies in humani- zed mice. Nature. (2012) (*equal contribution)

NOTES

70 | | 71 Melanie Greter Session 7 “Life and Fate of Brain Macrophages”

Institute of Experimental Immunology 5 SELECTED PUBLICATIONS University of Zurich, Zurich, Switzerland 1. Yu X, Buttgereit A, Lelios I, Utz S, Cansever D, Becher B, Greter M. The cytokine TGF-β promotes the development and maintenance of alveolar macrophages. Immunity. 2017 Nov 21;47(5):903-912.e4

BIOSKETCH 2. Buttgereit A, Lelios I, Yu X, Vrohlings M, Krakoski RN, Gautier EL, Nishinakamura R, Becher B, Gre- ter M. Sall1 is a transcriptional regulator defining microglia fate and function.Nat Immunol. 2016 Melanie and her team are interested in the development, regulation and function of mononuclear pha- Dec;17(12):1397-1406 gocytes in health and disease, with a specific focus on brain macrophages 3. Mrdjen D, Pavlolvic A, Hartmann FJ, Schreiner B, Utz S, Leung BP, Lelios I, Heppner FL, Kipnis J, Merk- Melanie Greter received her PhD at the University of Zurich from the Institute of Neuroimmunology in ler D, Greter M and Becher B. High-Dimensional Mapping of the Immune Atlas in the Central Nervous 2007. After her postdoctoral fellowship in Miriam Merad’s lab at the Mount-Sinai School of Medicine in System During Health, Aging and Disease Immunity. 2018 Feb 20;48(2):380-395.e6 New York, she moved back to Zurich to establish her own group in 2011. Since 2013, she is an SNSF (Swiss National Science Foundation) professor in the Institute of Experimental Immunology at the University 4. Greter M, Lelios I, Pelczar P, Hoeffel G, Price J, Leboeuf M, Kündig TM, Frei K, Ginhoux F, Merad M, of Zurich. Becher B. Stroma-derived IL-34 controls the development and maintenance of Langerhans cells and the maintenance of microglia. Immunity, 2012 Dec 14;37(6):1050-60

ABSTRACT 5. Ginhoux F, Greter M, Leboeuf M, Gouon-Evans V, Stanley RE, Samokvalov IM, Merad M. Fate map- ping studies reveal that adult microglia derive from primitive macrophages. Science, 2010 Nov Central nervous system (CNS) macrophages comprise parenchymal microglia and border-associated 5;330(6005):841-5 macrophages (BAMs) residing in the meninges, the choroid plexus and the perivascular spaces. With the exception of the more heterogeneous choroid plexus macrophages, they mostly emerge from early erythro-myeloid precursors in the extra-embryonic yolk sac. Whether these distinct brain macropha- ges share a developmental program or arise from individual predefined pathways is not clear. Here, we identified two phenotypically, transcriptionally and locally distinct brain macrophage populations throughout development, giving rise to microglia and BAMs. Two separate macrophage populations were already existent in the yolk sac prior to their seeding of the brain. The differentiation of microglia was dependent on the receptor for TGF-β during development whereas the genesis and maturation of BAMs occurred independently of this cytokine. Collectively, our data show that developing parenchymal and non-parenchymal brain macrophages represent independent entities in terms of ontogeny, gene expression profiles and requirement for TGF-β. NOTES

72 | | 73 Frédéric Geissmann Session 8 “Genetic and developmental basis for macrophages functions”

Immunology Program, Sloan Kettering Institute Memorial Sloan Kettering Cancer Center, New York, USA NOTES

5 SELECTED PUBLICATIONS

1. Jacome-Galarza CE, Percin GI, Muller JT, Mass E, Lazarov T, Eitler J, Rauner M, Yadav VK, Crozet L, Bohm M, Loyher PL, Karsenty G, Waskow C Geissmann F. Developmental origin, functional main- tenance and genetic rescue of osteoclasts. Nature. 2019 Apr;568(7753):541-545. doi: 10.1038/s41586- 019-1105-7. Epub 2019 Apr 10.

2. Mass E, Jacome-Galarza CE, Blank T, Lazarov T, Durham BH, Ozkaya N, Pastore A, Schwabenland M, Chung YR, Rosenblum MK, Prinz M, Abdel-Wahab O, Geissmann F. A somatic mutation in erythro-mye- loid progenitors causes neurodegenerative disease. (2017) Nature 549(7672):389-393. doi: 10.1038/ nature23672. PMID: 28854169

3. Elvira Mass, Ivan Ballesteros, Matthias Farlik, Florian Halbritter, Patrick Gunther, Lucile Crozet, Christian E. Jacome-Galarza, Kristian Handler, Johanna Klughammer, Yasuhiro Kobayashi, Elisa Gomez-Perdiguero, Joachim L. Schultze, Marc Beyer, Christoph Bock, Frederic Geissmann. Speci- fication of tissue-resident macrophages during organogenesis (2016)Science . pii: aaf4238. PMID: 27492475 PMCID: PMC5066309

4. Stamatiades EG, Tremblay ME, Bohm M, Crozet L, Bisht K, Kao D, Coelho C, Fan X, Yewdell WT, David- son A, Heeger PS, Diebold S, Nimmerjahn S, Geissmann F. Immune Monitoring of Trans Endothelial Transport by Resident Kidney Macrophages (2016) Cell 166: 991-1003. doi: 10.1016/j.cell.2016.06.058. Epub 2016 Jul 28. PMID: 27477514 PMCID: PMC4983224

5. Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K, Prinz M, Wu B, Ja- cobsen SE, Pollard JW, Frampton J, Liu KJ, Geissmann F. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. (2012) Science. 336:86-90. PMID: 22442384.

74 | | 75 Thomas Gebhardt Session 8 “A new melanoma platform to study spontaneous immunity, cancer- immune equilibrium and immune control of metastatic disease”

Senior Medical Research Fellow (Sylvia & Charles Viertel Charitable Foun- 5 SELECTED PUBLICATIONS dation) Department of Microbiology & Immunology, The University of Mel- bourne | Peter Doherty Institute for Infection and Immunity, Victoria, 3000 1. Gebhardt T, Wakim LM, Eidsmo LA, Reading PC, Heath WR, Carbone FR. Non-lymphoid tissue-resi- Melbourne, Australia dent memory T cells that provide enhanced local immunity in HSV infection. Nat Immunol 2009 (10:524–530). Citations: 545

BIOSKETCH 2. Gebhardt T, Whitney PG, Zaid A, Mackay LK, Brooks AG, Heath WR, Carbone FR, Mueller SN. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 2011 (477:216–219). Cita- Thomas is a laboratory head in the Department of Microbiology and Immunology at the Peter Doherty tions: 287 Institute for Infection and Immunity, the University of Melbourne. His team studies basic and trans- lational aspects of immune responses in peripheral tissues. Their work pioneered the discovery and 3. Mackay LK, Stock AT, Ma JZ, Jones CM, Kent SJ, Mueller SN, Heath WR, Carbone FR, Gebhardt T. transcriptional and functional characterisation of tissue-resident memory T cells (TRM), a population Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting of T cells now widely regarded as key mediators of protective immunity in barrier tissues. More recent- local antigen presentation. Proc Natl Acad Sci USA 2012 (109:7037–7042). Citations: 273 ly, they described the important function of TRM cells in controlling clinically occult melanoma. The overall goal of Thomas’ team is to understand the function of TRM cells in health and disease and to 4. Mackay LK, Rahimpour A, Ma JZ, Collins N, Stock AT, Hafon ML, Vega-Ramos J, Lauzurica P, Mueller develop vaccines and immunotherapies that target TRM cells for improved clinical outcomes in infec- SN, Stefanovic T, Tscharke DC, Heath WR, Inouye M, Carbone FR, Gebhardt T. The development tion, inflammation and cancer. pathway for CD103+CD8+ tissue-resident memory T cells of skin. Nat Immunol 2013 (14:1294–1301). Thomas received training in clinical medicine and biomedical research at the Hanover Medical School, Citations: 399 Germany, before joining the University of Melbourne in 2005. Over the years, he has been supported by a postdoctoral fellowship from the German Research Foundation, a RD Wright Career Development 5. Park SL, Buzzai A, Rautela J, Hor JL, Hochheiser K, Effern M, McBain N, Wagner T, Edwards J, McCon- Award (NHMRC) and a CR Roper Fellowship (University of Melbourne), and currently holds the prestigi- ville R, Wilmott JS, Scolyer RA, Tüting T, Palendria U, Gyorki D, Mueller SN, Huntington ND, Bedoui ous Senior Medical Research Fellowship from the Sylvia & Charles Viertel Charitable Foundation. S, Hölzel M, Mackay LK, Waithman J, Gebhardt T. Tissue-resident memory CD8+ T cells promote melanoma-immune equilibrium in skin. Nature 2019 (565:366-371). Citations: 14

ABSTRACT

Tissue-resident memory T cells promote melanoma-immune equilibrium The immune system can fight cancer by eliminating malignant cells or by preventing the outgrowth and spread of cancer cells that resist immune eradication. The nature and spatiotemporal dynamics of immune responses that efficiently control persisting cancer cells however have remained elusive. We have developed a transplantable melanoma model that approximates distinct disease stages seen in patients, including progressively growing tumours with metastatic spread, stably controlled tumours NOTES and long-term persistence of occult melanoma cells in absence of tumours. We have built key techno- logies around this model, including in vivo and ex vivo imaging techniques, as well as a gene editing platform that we are using to generate melanoma variants tailored to address defined experimental questions. Combined, these tools uniquely permit tracking, manipulation and imaging of melanoma and tumour-specific T cells, including a direct visualisation of localised T-cell-mediated tumour sup- pression. We are currently using this set-up to elucidate the contribution of tissue-resident memory T cells and other immune cells to the durable control of cutaneous melanoma and metastatic disease, and to uncover basic molecular pathways involved in efficient tumour suppression. Such fundamental knowledge that has the potential to guide the development and improvement of future cancer immuno- 76 | therapies. | 77 Michael Dustin Session 8 “Supramolecular attack particles: a new cytotoxic biomaterial”

Professor of Immunology and Wellcome Trust Principal Research Fellow SMAPs lack TCR, but appear to incorporate innate recognition molecules. I will describe the compositi- The Kennedy Institute of Rheumatology on, structure and function of SYNECTs and SMAPs and discuss potential applications. University of Oxford 5 SELECTED PUBLICATIONS BIOSKETCH 1. Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML. The immunological synap- Dr. Dustin is a basic scientist with a focus on understanding interactions between cells of the immune se: a molecular machine controlling T cell activation. Science. 1999;285(5425):221-7. PubMed PMID: system. He joined the University of Oxford in 2013 after working for 13 years at NYU School of Medicine 10398592. and 7 years at Washington University School of Medicine. Dr. Dustin’s work on basic mechanisms of immune cell function began when he was a graduate student with Timothy Springer at Harvard Medical 2. Somersalo K, Anikeeva N, Sims TN, Thomas VK, Strong RK, Spies T, Lebedeva T, Sykulev Y, Dustin ML. School, where he described links between innate and adaptive immunity through regulation of adhesi- Cytotoxic T lymphocytes form an antigen-independent ring junction. J Clin Invest. 2004;113(1):49-57. on molecules. His work at Washington University led to the first dynamic description of immunological PubMed PMID: 14702108. synapse, work recognized by a Presidential Early Career Award in Science and Engineering. At NYUSOM, Dr. Dustin continued innovative studies of the immunological synapse, including discovery of synaptic 3. Choudhuri K, Llodra J, Roth EW, Tsai J, Gordo S, Wucherpfennig KW, Kam LC, Stokes DL, Dustin ML. ectosomes as a new messenger in the immune system, and has imaged the immunological synapse in Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse. Nature. vivo. At the Kennedy Institute of Rheumatology in Oxford he has undertaken a program to develop the- 2014;507(7490):118-23. Epub 2014/02/04. doi: 10.1038/nature12951. PubMed PMID: 24487619 rapies for autoimmune diseases. He has published over 300 peer reviewed papers and review articles. He has also authored several patents, one of which led to the first “biologic” drug approved for treat- 4. Papa I, Saliba D, Ponzoni M, Bustamante S, Canete PF, Gonzalez-Figueroa P, McNamara HA, Valvo ment of psoriasis. NIH has recognized his work through a Merit Award, presentation of the Director’s S, Grimbaldeston M, Sweet RA, Vohra H, Cockburn IA, Meyer-Hermann M, Dustin ML, Doglioni C, lecture and funding of a Nanomedicine Development Center (2008-2012). Dr. Dustin currently holds a Vinuesa CG. TFH-derived dopamine accelerates productive synapses in germinal centres. Nature. Wellcome Trust Principle Research Fellowship focusing on Translation of the Immunological Synapse, 2017;547(7663):318-23. doi: 10.1038/nature23013. PubMed PMID: 28700579 a European Research Council Advanced grant on synaptic ectosomes and a Human Frontiers Science Program grant on antibody formation. 5. Saliba DG, Cespedes-Donoso PF, Balint S, Compeer EB, Korobchevskaya K, Valvo S, Mayya V, Kvalvaag A, Peng Y, Dong T, Tognoli ML, O‘Neill E, Bonham S, Fischer R, Kessler BM, Dustin ML. Composition and structure of synaptic ectosomes exporting antigen receptor linked to functional CD40 ligand ABSTRACT from helper T-cells. eLife. 2019;8:600551. Epub 2019/08/31. doi: 10.7554/eLife.47528. PubMed PMID: 31469364. Supramolecular attack particles: a new cytotoxic biomaterial T cells communicate through direct cell-cell contact across gaps of only 13 nm (immunological synapse) or through secreted cytokines (1) or cytolytic proteins (2). I will present data from my lab on the role of CD2 expression in immunological synapse structure and on an intermediate mode of communication NOTES based on T cell export of vesicles and non-vesicular particles to antigen presenting cells across im- munological synapses. I will present data that CD2-CD58 interactions amplify TCR signals and the low CD2 expression has a similar impact to engaging PD1 on signaling parameters (https://www.biorxiv.org/ content/ 10.1101/589440v1). Vesicles that are generated in the immunological synapse by budding from the plasma membrane into the extracellular space are referred to as synaptic ectosomes (SYNECT) (3- 5). SYNECTs combine both antigen recognition and effector function and thus may maintain specificity even if they escape the initial synaptic interaction. In contrast, cytotoxic CD8+ T cells release non-lipid bilayer enveloped cytotoxic microparticles into the synaptic cleft (Balint, Fisher, Kessler. Harkiolaki and Dustin, in preparation). SMAPs are held together by multiple non-covalent protein-protein and pro- 78 | tein-carbohydrate interactions and are referred to as supramolecular attack particles (SMAPs). | 79 Notes Notes

80 | | 81 MapSymposium – Future of Immunology @ Berlin Charité – Universitätsmedizin Berlin | Campus Charité Mitte

120 / N20 Hessische Str. Adina Apartment Hotel Invalidenstr. Berlin Mitte 120/123/142/147/ M5 / M8 / M10 245 / M41/ M85/ N20/ N40/TXL 142/ 147/ 245/ N40/TXL1 TXL/142 Hannoversche Ha 55 nn Str. o v Robert-Koch- Str. e 3/5/ 7/9 r Hufelandweg Platz sc h M5 / M8 / M10 e

142 Berlin - Hauptbahnhof Rahel- R Hirsch- a Weg h e Philippstr. l- H

i r s c h -

Hörsaalruine W

e g

Alexander- 147/ 245

2 H u Bonhoefferweg f e - Sauerbruchweg 3

Luisenstr.

l

a

n

d

Virchowweg - Wilhelm-

ufer Waldeyer

Haus

w

e

g

Margarete-Steffin-Str. 6 147/ 245 Charité- platz 1/2/3/5/7/9/25/26 Schumannstr. M1 / 12 Friedrichstraße Charitéstr. Ka Oranienburger Tor pe lle -U 147 f er Karl-

- str. platz Reinhardtstr. 245

1 Adina Apartment Hotel Unterbaum 2 Hörsaalruine Marschallbrücke3 Wilhelm-Waldeyer Haus Berlin Mitte Visiting address Philippstraße 12, 10115 Berlin Platz vor dem Neuen Tor 6 Virchowweg 16 The gate entrance on the right next to Luisenstr. 57 using 10115 Berlin the path follow the path into the park area and keep left. After approx. 100 m you will reach the main entrance to Wilhelm-Waldeyer Haus (Center for Anatomy). Gestaltung: Zentrale Mediendienstleistungen, Charité – Universitätsmedizin Berlin 82 | GB-Strategische-Unternehmensentwicklung > Symposium > future-of-immunology > Booklet_A5.indd https://future-of-immunology-berlin.charite.de/en/ e-mail: [email protected] | 83