The University of Oxford Immunology Network, in collaboration with the British Society for Immunology's Oxford Immunology Group
OXFORD IMMUNOLOGY SYMPOSIUM 2021
20 -22 APRIL 2021 Oxford Immunology Symposium 2021 20 – 22 April 2021
Tuesday 20 April
09:30 Welcome Paul Klenerman, University of Oxford, UK
SESSION 1 Chairs: Paul Klenerman, University of Oxford, UK and Alexandra Spencer, University of Oxford, UK
09:35 Macrophages in type 2 immunity: learning from tissue-dwelling worms Judi Allen, University of Manchester, UK
10:25 AhR sensing bacterial quorum during infection Pedro Moura Alves, University of Oxford, UK
10:45 Comfort break
10:55 Interrogating the roles of Alzheimer's and Parkinson's associated genes in iPS-macrophages and microglia Sally Cowley, University of Oxford, UK
11:15 Retinyl Esters: A new family of CD1a ligands? Ciara Maguire, University of Oxford, UK – selected short talk
11:25 Distinct developmental pathways from blood monocytes generate human lung macrophage diversity Tim Willinger, Karolinska Institutet, Sweden – selected short talk
11:35 Using innate immune ligands to activate adaptive immune cells for Glioblastoma therapy Richard Baugh, University of Oxford, UK – selected short talk
11:45 Close Wednesday 21 April
SESSION 2 Chairs: Jelena Bezbradica Mirkovic, University of Oxford, UK and Athena Cavounidis, University of Oxford, UK
14:00 Using genetics to investigate adaptive immune responses in health & disease Rachael Bashford-Rogers, University of Oxford, UK
14:20 SARS-CoV-2 responses in people living with HIV Dimitra Peppa, University of Oxford, UK
14:40 Circadian regulation of SARS-CoV-2 infection in lung epithelial cells Mirjam Schilling, University of Oxford, UK – selected short talk
14:50 Immune spatial heterogeneity within critical COVID-19 patient lungs Amy Cross, University of Oxford, UK – selected short talk
15:00 Comfort break
15:10 Molecular mechanisms and role of exhausted CD8 T cells in disease John Wherry, University of Pennsylvania, USA
16:00 Close
Thursday 22 April
SESSION 3 Chairs: Audrey Gerard, University of Oxford, UK and Alexandra Spencer, University of Oxford, UK
09:30 Regulation of T cell fate diversity Annette Oxenius, ETH Zurich, Switzerland
10:20 Autophagy-mediated transition of interleukin signalling is crucial to CD4+ T cell proliferation Dingxi Zhou, University of Oxford, UK – selected short talk
10:30 Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice Dominik Aschenbrenner, University of Oxford, UK – selected short talk
10:40 Characterisation of iron dependent pathways in T-cells Megan Teh, University of Oxford, UK – selected short talk
10:50 Comfort break
11:00 A MAIT cell journey, from Salmonella to COVID Mariolina Salio, University of Oxford, UK
11:20 The role of MAIT cells in regulating vaccine immunogenicity Nicholas Provine, University of Oxford, UK
11:40 Closing remarks
11:45 Close
Speakers’ biographies
Judi Allen, University of Manchester, UK Judi Allen obtained her PhD from the University of California, Berkeley following several years in the Biotech Industry. For her postdoc she moved to Imperial College, London and began her work on the immune response to helminths in Rick Maizels’ lab. The host response to tissue-dwelling nematodes and the associated type 2 immune response has remained the focus of her research career. In 1997, Judi established her own group at the University of Edinburgh with an MRC Senior Fellowship and became Professor of Immunobiology in 2005. In 2016, Judi joined the Faculty of Biology, Medicine & Health at the University of Manchester. Judi is a Fellow of the Royal Society of Biology, the Royal Society of Edinburgh and the Academy of Medical Sciences and a member of EMBO. She is best known for her work on the biology of macrophages in the context of macroparasite infection and is particularly interested in the relationship of type 2 immunity to wound repair pathways.
Dominik Aschenbrenner, University of Oxford, UK To explore the cellular and molecular networks of the human immune system and to understand key biologic processes that maintain the balance between the host response and the environment is simply fascinating. Immunology has been the central focus throughout Dominik’s academic career at the University of Vienna, the ETH Zurich, and the University of Oxford during which he had the chance to explore diverse areas of basic and translational research including vaccinology, TH17 biology, mucosal immunology and primary immunodeficiency.
Rachael Bashford-Rogers, Wellcome Centre for Human Genetics, University of Oxford, UK Rachael did her PhD at Wellcome Sanger Institute where she developed methods for B and T cell receptor sequencing for characterising adaptive immune responses in health, leukaemia and infectious disease. Then she went onto win the Sir Henry Wellcome Fellowship in University of Cambridge working on characterising B cell dysfunction in autoimmune diseases and the effects of different immunomodulatory therapies. Now she is a group leader at the Wellcome Centre of Human Genetics at the University of Oxford. Her lab is developing and exploiting novel experimental and computational methods to decipher the mechanistic basis of immune cell regulation across immunological diseases and cancers from novel perspectives to provide insights for guiding better therapeutics.
Richard Baugh, University of Oxford, UK As an undergraduate, Richard studied Molecular and Cellular Biochemistry at the University of Oxford before graduating in 2017. He was then awarded a personal studentship by Brain Research UK to pursue a DPhil with the Seymour group at the Department of Oncology, University of Oxford, investigating novel ways to enhance oncolytic virotherapy for the treatment of glioblastoma brain tumours, where he is now in his fourth and final year of study.
Sally Cowley, Sir William Dunn School of Pathology, University of Oxford, UK Sally Cowley joined the Sir William Dunn School of Pathology as a Wellcome Trust Career Re- Entry Fellow in 2007, engaged in a program of research into the differentiation of human Pluripotent Stem Cell-derived macrophages and their applications for HIV studies. With William James, she set up the James Martin Stem Cell Facility, affiliated to the Oxford Stem Cell Institute, for work with human Pluripotent Stem cells. Collaborative projects she works on within this facility include: iPSc-derived macrophages as a genetically-modifiable model system for understanding macrophage biology; developing iPSc- microglia to study the contribution of microglia to neurodegenerative disease; generating iPS cells from Parkinson’s Disease patients as part of a large scale Oxford Parkinson’s Disease Centre research programme funded by Parkinson’s UK; EU IMI StemBANCC, which established a panel of iPS derived cell lines from 500 patients as a platform for cellular phenotypic drug screening with industry partners; MRC DPUKExperimental Medicine Dementia Stem Cell Network, a UK-wide network (Oxford, Cambridge, UCL, Manchester, Cardiff, Edinburgh) using iPSc for modelling dementia. https://www.wsjlab.com/meet-the-lab/sally-cowley/
Amy Cross, University of Oxford, UK Amy is a postdoctoral researcher in the Transplantation Research and Immunology Group (TRIG) at the University of Oxford. She did her PhD at the Université Sorbonne Paris Cité, where she explored mechanisms driving alloimmunity and chronic rejection. Her current research explores therapeutic strategies for establishing lasting tolerance towards allografts, and spatial transcriptomic techniques to better dissect pathology in human tissue.
Ciara Maguire, University of Oxford, UK Ciara is a dermatology specialty trainee in London, having received her medical degree from Trinity College Dublin. She is currently undertaking a DPhil in Professor Graham Ogg's Lab at the MRC Weatherall Institute of Molecular Medicine, University of Oxford. Her project focusses on the identification of neolipid antigens for CD1a in the context of psoriasis and the characterisation of CD1a- reactive T cells.
Pedro Moura-Alves, Ludwig Institute, University of Oxford, UK Dr. Moura-Alves studied Biochemistry at Universidade da Beira Interior (Covilhã, Portugal), graduating in 2004. As an undergraduate student, he undertook a research project at the University of Utrecht (The Netherlands). After, he joined the Graduated Program in Areas of Basic and Applied Biology (GABBA) at the University of Porto (Portugal). In 2005, Pedro moved to Boston (USA) to start his PhD research project, joining the group of Prof. Dr. Bruce Walker (Partners AIDS Research Center/Massachusetts General Hospital/ Harvard Medical School), to study the role of antigen processing machinery in immunity to HIV infection. In 2007, he joined the group of Dr. Luís Ferreira Moita (Instituto de Medicina Molecular- João Lobo Antunes, Lisboa, Portugal) to study the role of Alternative Splicing in the regulation of inflammatory responses. After finishing his PhD in 2010, Dr. Moura Alves joined the group of Prof. Dr. Stefan Kaufmann at the Max Planck Institute for Infection Biology (Berlin, Germany), as a postdoctoral fellow, focusing on the role of the Aryl Hydrocarbon Receptor (AHR) in sensing and shaping immune responses to bacterial infections. As of March 2019, Dr. Moura Alves is a group leader at the Ludwig Institute for Cancer Research/University of Oxford (Oxford, UK), exploring whether mechanisms that sense and regulate immune responses to microbial insults, also impact on cancer and therapeutic interventions. The main aim of the Moura Alves laboratory is to understand the AHR functions in infection and cancer, with the long-term goal of targeting AHR responses tailored to a specific disease and/or disease stage to improve disease treatment and patient outcomes.
Annette Oxenius, ETH Zurich, Switzerland Annette Oxenius is an immunologist and heads the Infection Immunology group at the Institute of Microbiology at ETH Zurich. She studied biochemistry at the University of Zurich and did her PhD with Hans Hengartner and Rolf Zinkernagel in the field of CD4 T cell immunology in the context of viral infections. She performed her postdoctoral work with Rodney Phillips at Oxford University where she studied human T cell immunity in HIV-1 infection. In 2002, she was appointed assistant professor for Immunology at the Institute of Microbiology at ETH Zurich and was promoted to full professor in 2012. Using experimental infection models in mice, Annette and her team investigate the regulation of adaptive immunity in the context of acute and chronic viral infections and its relevance for viral control or avoidance of severe immunopathology. Currently, a major research focus is to understand the role of virus-specific CD4 responses during chronic viral infections to support continuous adaptation of virus- specific humoral immunity with the aim to delineate the evolution of virus-specific antibodies in face of a concomitantly evolving viral genome / proteome using systems-immunological approaches. An additional research focus is to dissect the mechanisms that regulate fate decisions of activated T cells with a particular interest in the role of asymmetric cell division in this process. Finally, Annette and her team study the cellular and molecular processes that support memory CD8 T cell inflation during cytomegalovirus infection, a phenomenon that has generated interest in CMV-based vectors for vaccine purposes.
Dimitra Peppa, Nuffield Department of Medicine, University of Oxford, UK Dimitra has dual training in basic science and medicine and a strong interest in the multifaceted clinical and scientific aspects of viral infection. Dimitra completed her medical and postgraduate training at UCL and joined University of Oxford on an MRC Clinician Scientist Fellowship. Her lab focuses on human T cell and NK cell biology, studying their role in the context of chronic viral infections (HIV, HBV) and more recently SARS-CoV-2 infection. The aim of Dimitra’s group is to underpin the molecular and cellular mechanisms that dictate immune cell antiviral capacity, informing the development of new therapeutic interventions. Currently she is funded by the NIH to advance HBV/HIV co-infection cure strategies.
Nicholas Provine, Translational Gastroenterology Unit, University of Oxford, UK Nicholas joined Professor Paul Klenerman’s group as a postdoctoral fellow in the spring of 2016. His research has focused on defining the functionality and regulation of innate-like T cells – T cell populations that are capable of executing effector functions in response to T cell-receptor (TCR)- independent stimulation. His work in this area has contributed to the identification of V2-expressing T cells as a member of this functional group. His primary focus has been on the role of these cells in regulating the immunogenicity of adenovirus vector vaccines. Nicholas is currently involved in the Wellcome Human Cell Atlas project and the OCTAVE clinical trial, which is examining the immunogenicity of the Oxford/Astrazeneca COVID-19 vaccine in individuals with IBD. Through these studies he hopes to gain a better understanding of the processes regulating the immunogenicity of this vaccine. Before coming to Oxford, Nicholas earned his B.Sc. in Microbiology from the University of Washington. During his studies, he worked in the labs of Professors Nancy Haigwood and Julie Overbaugh, where he studied the impact of construction technique on the biochemical and functional properties of HIV virions. In 2015, Nicholas earned his Ph.D. in Virology from Harvard University. He performed his thesis research in the laboratory of Professor Dan Barouch, where he studied the role of CD4+ T cells in regulating the cellular and humoral immune responses induced by adenovirus vector vaccines.
Mariolina Salio, MRC Human Immunology Unit, University of Oxford, UK Mariolina graduated in Medicine at the University of Torino, Italy, after spending some time as a visiting research student at Mount Sinai Medical School (New York) and Harvard Medical School (Boston). She then joined the lab of Prof Antonio Lanzavecchia at the Basel Institute for Immunology in 1996, to work on human Dendritic Cells, within the EUNIDI network (European Union Network for Investigation of Dendritic Cell Immunotherapy). Mariolina moved to Oxford at the end of 1999 and joined the group of Prof Vincenzo Cerundolo in the MRC Human Immunology Unit. Her main research interest is understanding how Dendritic Cells, the “specialized” antigen presenting cells of the immune system orchestrate immune responses and efficiently prime antigen specific T cells. Specifically, she is interested in understanding how subset of immune cells known as innate-like T cells or unconventional T cells modulate Dendritic Cell activation and T cell priming. The two main subsets of innate like T cells Mariolina has been studying are CD1d-restricted iNKT cells and MR1-restricted MAIT cells, which recognize non-peptidic antigens. As a senior scientist in the MRC Human Immunology Unit in Oxford, through a range of cellular and molecular cutting edge techniques, Mariolina aims to harness the power of innate-like T cells, to enhance immune responses to infections and cancer.
Mirjam Schilling, University of Oxford, UK Mirjam Schilling is a Postdoctoral Researcher in Jane McKeating’s lab in the Nuffield Department of Medicine in Oxford. After a Postdoc in Jan Rehwinkel’s group in Oxford, where she studied the innate immune sensing of ZIKV, her current work focuses on the interplay of hypoxia and circadian rhythms with innate immune responses.
Megan Teh, University of Oxford, UK Megan Teh is a second year DPhil student in the Drakesmith lab within the MRC HIU at the MRC WIMM, who is interested in the role of iron in T-cell biochemistry. She received her BSc from McGill University in 2019 with first class Honours in Microbiology and Immunology. Megan has previously worked on winter tick in moose and caribou and host Salmonella susceptibility genetics.
John Wherry, University of Pennsylvania, USA Dr. E. John Wherry is the Barbara and Richard Schiffrin President’s Distinguished Professor, Chair of the Department of Systems Pharmacology and Translational Therapeutics in the Perelman School of Medicine and Director of the UPenn Institute for Immunology. Dr. Wherry received his Ph.D. at Thomas Jefferson University in 2000 then did postdoctoral research at Emory University with Dr. Rafi Ahmed from 2000-2004. Dr. Wherry has received numerous distinctions and honors including the Distinguished Alumni award from the Thomas Jefferson University, the Cancer Research Institute’s Frederick W. Alt Award for New Discoveries in Immunology and the Stand Up To Cancer Phillip A. Sharp Award. Dr. Wherry has over 225 publications. He has an H-Index of 101 and his publications have been cited over 55,000 times.
Dr. Wherry’s research has pioneered the field of T cell exhaustion – the fundamental mechanisms by which T cell responses are attenuated during chronic infections and cancer. His discoveries helped identify the role of PD-1 and the ability to block this pathway to reinvigorate exhausted T cells. His group also first demonstrated that targeting multiple co-inhibitory receptors simultaneously could synergistically improve therapeutic efficacy, a foundation for current combination immunotherapy efforts in humans. Dr. Wherry’s work has defined the transcriptional and epigenetic atlas of exhausted T cells defining exhausted T cells as a distinct immune lineage. Finally, his laboratory has been a pioneer in defining the concept of Immune Health using systems immunology approaches, most recently applying this concept to COVID-19.
Tim Willinger, Karolinska Institutet, Sweden Tim Willinger is an Associate Professor at Karolinska Institutet. He did his scientific training in immunology at Oxford and Yale University with Andrew McMichael and Richard Flavell. He has developed novel experimental models to study the human immune system in vivo (humanized mice). His research group studies immune responses in mucosal tissues with a focus on macrophages and innate lymphoid cells.
Dingxi Zhou, University of Oxford, UK Dingxi Zhou is a DPhil student at the Kennedy Institute of Rheumatology, the University of Oxford. Under the supervision of Professor Katja Simon, he is interested in studying how autophagy modulates various physiological processes and diseases, especially the immune cell senescence. Dingxi aims to unravel more potential therapeutic targets, and further to translate the fundamental scientific discoveries into clinical applications.
Abstracts: selected short talks
Retinyl Esters: A new family of CD1a ligands? CA Maguire, YL Chen, J Woo, R Singh, R Etherington, G Ogg MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, UK Psoriasis is a common, chronic inflammatory skin disease characterised by cytokines including interferon gamma, IL-22 and IL-17A/F. Epidermal Langerhans cells express CD1a, an MHC-I-like molecule, which presents both self- and foreign lipid antigens to T cells. Although only a limited number of these antigens have been defined, it is clear that CD1a contributes to inflammatory skin disease pathogenesis. Retinoic acid antagonises many of the features seen in psoriasis; and genes involved in retinoid metabolism, transport and binding are altered in psoriasis while retinoids have been used as treatment. RNA-Sequencing analysis was performed on biopsies from patients with psoriasis (n=15) exposed to different treatments, atopic dermatitis (n=5) and healthy controls (n=5). Retinoid-related genes were altered in psoriatic skin and their change in expression as disease resolved varied depending on therapeutic modality. Based on chemical structure, we investigated retinyl esters (RE), as candidate ligands for CD1a. IEF gels demonstrated that RE bind to CD1a and may displace known ligands. Specific RE inhibited interferon gamma secretion by CD1a-autoreactive T cell clones. Therefore, we suggest that RE can be added as a new family of inhibitory CD1a ligands. Their loss may provide early signals of a stressed state, promoting autoreactivity and psoriatic inflammation.
Distinct developmental pathways from blood monocytes generate human lung macrophage diversity Elza Evren1, Emma Ringqvist1, Kumar Parijat Tripathi1, Natalie Sleiers1, Inés Có Rives1, Arlisa Alisjahbana1, Yu Gao1, Dhifaf Sarhan1, Tor Halle2, Chiara Sorini1, Rico Lepzien1, Nicole Marquardt1, Jakob Michaëlsson1, Anna Smed-Sörensen1, Johan Botling2, Mikael C. I. Karlsson1, Eduardo J. Villablanca1, Tim Willinger1 1Karolinska Institutet, Sweden; 2Uppsala University, Sweden The study of human macrophages and their ontogeny is an important unresolved issue. Here, we use a humanized mouse model expressing human cytokines (called “MISTRG”) to dissect the development of lung macrophages from human hematopoiesis in vivo. Human CD34+ hematopoietic stem and progenitor cells (HSPCs) generated three macrophage populations, occupying separate anatomical niches in the lung. Intravascular cell labeling, cell transplantation, and fate-mapping studies established that classical CD14+ blood monocytes derived from HSPCs migrated into lung tissue and gave rise to human interstitial and alveolar macrophages. In contrast, non-classical CD16+ blood monocytes preferentially generated macrophages resident in the lung vasculature (pulmonary intravascular macrophages). Finally, single-cell RNA-sequencing defined intermediate differentiation stages in human lung macrophage development from blood monocytes. This study identifies distinct developmental pathways from circulating monocytes to lung macrophages and reveals how cellular origin contributes to human macrophage identity, diversity, and localization in vivo.
Using innate immune ligands to activate adaptive immune cells for Glioblastoma therapy Richard Baugh, Hena Khalique, Janet Lei-Rossmann, Len Seymour University of Oxford Glioblastoma (GBM) is a highly aggressive brain tumour. Despite conventional therapy of surgical resection, radiotherapy and temozolomide (TMZ) chemotherapy, tumours invariably recur and become resistant. The Natural Killer Group 2 Member D (NKG2D) receptor plays a key role in innate immune control of cancers. The ligands for this receptor (NKG2DLs) are minimally expressed or absent on healthy cells. Stressed or malignant cells upregulate NKG2DLs, resulting in immune activation. We have developed a strategy targeting upregulated NKG2DLs on GBM cells with bi-specific T cell engagers (BiTEs). NKG2D-BiTE contains a recombinant NKG2D receptor linked to an anti-CD3 domain. Simultaneous binding of the NKG2D-BiTE to NKG2DLs on GBM cells and CD3 on T cells causes antigen- independent activation, pro-inflammatory cytokine release, and tumour cell death. Pre-treating GBM cells with radiation and TMZ causes further NKG2DL upregulation, increased NKG2D-BiTE-mediated T cell activation, and sensitises GBM cells to T cell lysis. Meanwhile, healthy non-cancer cells exposed to the same pre-treatment do not trigger T cell activation with NKG2D-BiTE. Combining conventional radio/chemotherapy with NKG2D-BiTE immunotherapy presents an opportunity for synergy by enhancing NKG2DL expression on GBM cells and directing T cell lysis specifically towards these tumour cells, whilst avoiding responses towards non-cancerous cells.
Circadian regulation of SARS-CoV-2 infection in lung epithelial cells Xiaodong Zhuang, Senko Tsukuda, Mirjam Schilling, Peter AC Wing, Claudia Orbegozo Rubio, Helene Borrmann, James M Harris, Jane A McKeating University of Oxford The COVID-19 pandemic, caused by SARS-CoV-2 coronavirus, is a global health issue with unprecedented challenges for public health. SARS-CoV-2 primarily infects cells of the respiratory tract, via binding human angiotensin-converting enzyme (ACE2) and infection can result in pneumonia and acute respiratory distress syndrome. Circadian rhythms coordinate an organism’s response to its environment and recent studies report a role for the circadian clock to regulate host susceptibility to virus infection. Influenza A infection of arhythmic mice, lacking the circadian component BMAL1, results in higher viral replication and elevated inflammatory responses leading to more severe bronchitis, highlighting the impact of circadian pathways in respiratory immune function. We demonstrate circadian regulation of ACE2 in lung epithelial cells and show that silencing BMAL1 reduces ACE2 expression and inhibits SARS-CoV-2 entry and RNA replication. Furthermore, we show an increased expression of interferon stimulated genes in BMAL1 silenced or REV-ERB agonist treated cells, providing one potential mechanism for circadian pathways to restrict virus infection. Our study suggests new approaches to understand and improve therapeutic targeting of COVID-19 and are translatable to other respiratory pathogens.
Immune spatial heterogeneity within critical COVID-19 patient lungs Amy Cross1, Stephen Sansom1, Ian Roberts1, Lucia Cerundolo1, Ignacio Melero2, Carlos Eduardo De Andrea2, Manuel Fortun Landecho2, Paul Klenerman1, Joanna Hester1, Fadi Issa1 1University of Oxford, UK; 2Universidad de Navarra, Spain Acute respiratory distress syndrome (ARDS) is a defining feature of severe infection with the SARS-CoV- 2 virus. This study aimed to characterise the immune landscape across the lungs of COVID-19 patients. Samples from three critical patients exhibited typical COVID-19 pathology with diffuse alveolar damage consistent with hyaline membrane and type II pneumocyte hyperplasia, interstitial inflammation, organising pneumonia and thrombi. All tissues tested positive for SARS-CoV-2 RNA using qPCR, whilst whole slide immunostaining revealed only few and sparsely distributed SARS-CoV-2 positive cells.
The transcript profile of selected areas of mild and severe diffuse alveolar damage was examined against the >1800 genes in the Cancer Transcriptome Atlas panel using the NanoString GeoMx Digital Spatial Profiling platform. Differential gene expression revealed histological severity associated with T cell activation, antigen presentation, cytotoxicity, and interferon gamma response pathways. Spatially- resolved cassettes of colocalised cell lineages and biological activity were described, highlighting the phenotype of key cell types and their relationship with signalling molecules. Spatial heterogeneity in transcriptional features was at least partially due to disparate histopathological damage. Accounting for this spatial heterogeneity allowed for the identification of a number of shared pathways across patients. Our data identify pathological immune targets that may be amenable to therapeutic intervention in critical disease.
Autophagy-mediated transition of interleukin signalling is crucial to CD4+ T cell proliferation Dingxi Zhou1, Ghada Alsaleh1, Mariana Borsa1, Susanne Zellner2, Daniel Puleston3, Sharon Sanderson4, Chrisitian Behrends2, Anna Katharina Simon1 1University of Oxford, UK; 2 Ludwig Maximilian University of Munich, Germany; 3Max Planck Institute, Germany; 4John Radcliffe Hospital, UK CD4+ T cells play a central role in adaptive immune function. During ageing, they show impaired proliferation and function, contributing to inadequate responses to infections and vaccines. We discovered that knocking out autophagy in CD4+ T cells mimics this ageing phenotype, demonstrating that autophagy contributes to keeping CD4+ T cells young. Mechanistically, it is unclear what autophagy needs to degrade selectively during CD4+ T cell proliferation. Thus, we created a novel mouse model to investigate this in primary cells based on the proximity labelling technique. It enables us to directly identify the autophagosomal content in most cell types by labelling proteins that neighbours LC3, a molecule enriched in autophagosomes. Among the molecules we identified with this model is IL-7Ra. We demonstrate that IL-7Ra is degraded via an LC3-positive compartment during TCR-mediated activation. Since IL-7Ra competes for the γc with IL-2R, accumulation of IL-7Ra on the surface of autophagy-deficient T cells impairs IL-2 signalling, which is indispensable for T cell proliferation. It indicates that autophagy can mediate the transition from cell survival by IL-7 to activation by IL-2. It further suggests that autophagy induction might be a way to enhance the immune function of aged individuals during vaccination or infections.
Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice Dominik Aschenbrenner1,2, Lin Wang3,4, Zhiyang Zeng5, SYK Study Group, Christoph Klein6, Bodo Grimbacher 7, 8, 9, 10, Kaan Boztug11, 12, 13, Ying Huang3, Dali Li5, Holm Uhlig1, 2, Aleixo Muise4, 14, 15, 16, 17 1Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford, Oxford, UK; 2Department of Pediatrics, John Radcliffe Hospital, Oxford, UK; 3Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children’s Hospital of Fudan University, Shanghai, China; 4SickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; 5Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China; 6Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig Maximilian University Munich, Munich, Germany; 7Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs- University of Freiburg, Freiburg, Germany; 8DZIF – German Center for Infection Research, Satellite Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany; 9CIBSS – Centre for Integrative Biological Signalling Studies, Albert-Ludwigs-University of Freiburg, Freiburg, Germany; 10RESIST – Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Albert- Ludwigs-University of Freiburg, Freiburg, Germany; 11Ludwig Boltzmann Institute for Rare and
Undiagnosed Diseases, St. Anna Children's Cancer Research Institute (CCRI), Medical University of Vienna, Vienna, Austria; 12CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Medical University of Vienna, Vienna, Austria; 13Department of Pediatrics and Adolescent Medicine, St. Anna Children’s Hospital, Vienna, Austria; 14Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada; 15Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; 16Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; 17Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. Spleen Tyrosine Kinase (SYK) is a critical immune signalling molecule and therapeutic target. While global knockout of Syk in mice is perinatally lethal and mice carrying a Syk-deficient haematopoietic system are protected from autoantibody-mediated arthritis and have a block in B cell development at the pro-B to pre-B cell transition, pathogenic variation of SYK has not been described in humans. We identified damaging mono-allelic SYK variants in six patients with immune deficiency, systemic disease such as colitis, arthritis and skin inflammation, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signalling indicating gain-of-function. A knock-in mouse model of a patient variant recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease.
Characterisation of iron dependent pathways in T-cells Megan R. Teh, Joe N. Frost, Andrew E. Armitage, Hal Drakesmith University of Oxford, UK; John Radcliffe Hospital, Oxford, UK Iron is required for effective adaptive immune responses (Frost et al., Med, 2021), and iron deficiency is the most common micronutrient deficiency worldwide. We re-analysed and combined pre-existing datasets, and performed experiments, to investigate the role of iron in T-cell function. We estimated T- cell iron content and predicted that T-cell iron requirements dramatically increase within 24 hours post- activation as T-cells reconfigure their metabolism. Our mathematical modelling further suggests that low serum iron, which occurs pathophysiologically during severe COVID-19 and chronic iron deficiency, may be unable to provide sufficient iron to support T-cell activation needs. We next bioinformatically identified sets of iron-interacting proteins in CD4+ and CD8+ T-cell proteomes throughout activation and differentiation to understand key iron-dependent mechanisms. Pathways including histone demethylation and oxidative phosphorylation were enriched with iron-interacting proteins, suggesting that iron deficiency may disproportionately impair these processes. Consistent with this, in vitro iron starved Th17 cells showed elevated expression of the repressive histone mark H3K27me3, which is usually removed by the iron-dependent lysine demethylases KDM6A and KDM6B. Iron depleted Th17s also displayed reduced RORγt and IL-17a expression highlighting a role for iron in T-cell differentiation. This work gives new directions to understand how iron deficiency influences adaptive immunity.
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