NK Cell Memory to Cytomegalovirus: Implications for Vaccine Development
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Killer-Like Receptors and GPR56 Progressive Expression Defines Cytokine Production of Human CD4+ Memory T Cells
ARTICLE https://doi.org/10.1038/s41467-019-10018-1 OPEN Killer-like receptors and GPR56 progressive expression defines cytokine production of human CD4+ memory T cells Kim-Long Truong1,7, Stephan Schlickeiser1,2,7, Katrin Vogt1, David Boës1, Katarina Stanko1, Christine Appelt1, Mathias Streitz1, Gerald Grütz1,2, Nadja Stobutzki1, Christian Meisel1, Christina Iwert1, Stefan Tomiuk3, Julia K. Polansky2,4, Andreas Pascher5, Nina Babel2,6, Ulrik Stervbo 6, Igor Sauer 5, Undine Gerlach5 & Birgit Sawitzki1,2 1234567890():,; All memory T cells mount an accelerated response on antigen reencounter, but significant functional heterogeneity is present within the respective memory T-cell subsets as defined by CCR7 and CD45RA expression, thereby warranting further stratification. Here we show that several surface markers, including KLRB1, KLRG1, GPR56, and KLRF1, help define low, high, or exhausted cytokine producers within human peripheral and intrahepatic CD4+ memory T-cell populations. Highest simultaneous production of TNF and IFN-γ is observed in KLRB1+KLRG1+GPR56+ CD4 T cells. By contrast, KLRF1 expression is associated with T-cell exhaustion and reduced TNF/IFN-γ production. Lastly, TCRβ repertoire analysis and in vitro differentiation support a regulated, progressive expression for these markers during CD4+ memory T-cell differentiation. Our results thus help refine the classification of human memory T cells to provide insights on inflammatory disease progression and immunotherapy development. 1 Institute of Medical Immunology, Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 13353 Berlin, Germany. 2 Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, 13353 Berlin, Germany. 3 Milteny Biotec GmbH, 51429 Bergisch Gladbach, Germany. -
Case of the Anti HIV-1 Antibody, B12
Spectrum of Somatic Hypermutations and Implication on Antibody Function: Case of the anti HIV-1 antibody, b12 Mesfin Mulugeta Gewe A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2015 Reading Committee: Roland Strong, Chair Nancy Maizels Jessica A. Hamerman Program Authorized to Offer Degree: Molecular and Cellular Biology i ii ©Copyright 2015 Mesfin Mulugeta Gewe iii University of Washington Abstract Spectrum of Somatic Hypermutations and Implication on Antibody Function: Case of the anti HIV-1 antibody, b12 Mesfin Mulugeta Gewe Chair of the Supervisory Committee: Roland Strong, Full Member Fred Hutchinson Cancer Research Center Sequence diversity, ability to evade immune detection and establishment of human immunodeficiency virus type 1 (HIV-1) latent reservoirs present a formidable challenge to the development of an HIV-1 vaccine. Structure based vaccine design stenciled on infection elicited broadly neutralizing antibodies (bNAbs) is a promising approach, in some measure to circumvent existing challenges. Understanding the antibody maturation process and importance of the high frequency mutations observed in anti-HIV-1 broadly neutralizing antibodies are imperative to the success of structure based vaccine immunogen design. Here we report a biochemical and structural characterization for the affinity maturation of infection elicited neutralizing antibodies IgG1 b12 (b12). We investigated the importance of affinity maturation and mutations accumulated therein in overall antibody function and their potential implications to vaccine development. Using a panel of point iv reversions, we examined relevance of individual amino acid mutations acquired during the affinity maturation process to deduce the role of somatic hypermutation in antibody function. -
The T Cell Repertoire Specific for the IE-1 Protein of Human Cytomegalovirus: Diversity, Function and Evasion
Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München The T cell repertoire specific for the IE-1 protein of human cytomegalovirus: diversity, function and evasion von Stefanie Maria Ameres aus Deggendorf, Deutschland 2012 Erklärung Diese Dissertation wurde im Sinne von §7 der Promotionsordnung vom 28. November 2011 von Herrn Prof. Dr. Wolfgang Hammerschmidt betreut und von Herrn Prof. Dr. Horst Domdey vor der Fakultät für Chemie und Pharmazie vertreten. Eidesstattliche Versicherung Diese Dissertation wurde eigenständig und ohne unerlaubte Hilfe erarbeitet. München, den 03.07.2012 Stefanie Ameres Dissertation eingereicht am 03.07.2012 1. Gutachter: Prof. Dr. Horst Domdey 2. Gutachter: Prof. Dr. Wolfgang Hammerschmidt Mündliche Prüfung am 28.01.2013 Teile dieser Arbeit werden/wurden wie folgt veröffentlicht: Ameres, S., J. Mautner, F. Schlott, M. Neuenhahn, D.H. Busch, B. Plachter, and A. Moosmann. Antigen Presentation to an Immunodominant Population of HLA-C-Restricted T Cells Resists Cytomegalovirus Immunoevasion. 2nd revision PLOS Pathogens Hesse, J., S. Ameres, K. Besold, S. Krauter, A. Moosmann, and B. Plachter. Suppression of CD8+ T-cell recognition in the immediate-early phase of human cytomegalovirus infection. Epub oct 2012. J. Gen. Virol. Teile dieser Arbeit wurden im Rahmen der Dissertation wie folgt präsentiert: May 3rd–4th, 2012 DFG SFB-TR36 Symposium "Adoptive T Cell Therapy" Berlin, Germany Talk: "CD8+ T cells overcome HCMV immunoevasion dependent on their HLA restriction" Dec. 5th–7th, 2011 DFG SFB-TR36 Retreat "Principles and Applications of Wildbad Kreuth, Adoptive T Cell therapy" Germany Talk: "CD8+ T cells defeat HCMV immunoevasins dependent on MHC restriction" May 14th–17th, 2011 13th International CMV/Betaherpesvirus Workshop Nürnberg, Germany Poster 1: "Preferential T cell control of HCMV infection through HLA-C" Poster 2: "HCMV IE-1 is recognized by a diverse repertoire of CD4+ Tcells" Oct. -
Single-Cell Profiling Identifies Impaired Adaptive NK Cells Expanded After HCMV Reactivation in Haploidentical HSCT
Single-cell profiling identifies impaired adaptive NK cells expanded after HCMV reactivation in haploidentical HSCT Elisa Zaghi, … , Enrico Lugli, Domenico Mavilio JCI Insight. 2021;6(12):e146973. https://doi.org/10.1172/jci.insight.146973. Research Article Hematology Immunology Graphical abstract Find the latest version: https://jci.me/146973/pdf RESEARCH ARTICLE Single-cell profiling identifies impaired adaptive NK cells expanded after HCMV reactivation in haploidentical HSCT Elisa Zaghi,1 Michela Calvi,1,2 Simone Puccio,3 Gianmarco Spata,1 Sara Terzoli,1 Clelia Peano,4 Alessandra Roberto,3 Federica De Paoli,3 Jasper J.P. van Beek,3 Jacopo Mariotti,5 Chiara De Philippis,5 Barbara Sarina,5 Rossana Mineri,6 Stefania Bramanti,5 Armando Santoro,5 Vu Thuy Khanh Le-Trilling,7 Mirko Trilling,7 Emanuela Marcenaro,8 Luca Castagna,5 Clara Di Vito,1,2 Enrico Lugli,3,9 and Domenico Mavilio1,2 1Unit of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. 2BIOMETRA, Università degli Studi di Milano, Milan, Italy. 3Laboratory of Translational Immunology, 4Institute of Genetic and Biomedical Research, UoS Milan, National Research Council, and Genomic Unit, 5Bone Marrow Transplant Unit, and 6Molecular Biology Section, Clinical Investigation Laboratory, IRCCS Humanitas Research Hospital, Milan, Italy. 7Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. 8Department of Experimental Medicine, University of Genoa, Genoa, Italy. 9Flow Cytometry Core, IRCCS Humanitas Research Hospital, Milan, Italy. Haploidentical hematopoietic stem cell transplantation (h-HSCT) represents an efficient curative approach for patients affected by hematologic malignancies in which the reduced intensity conditioning induces a state of immunologic tolerance between donor and recipient. -
Natural Killer Cells in Antiviral Immunity
REVIEWS Natural killer cells in antiviral immunity Niklas K. Björkström ✉ , Benedikt Strunz and Hans- Gustaf Ljunggren Abstract | Natural killer (NK) cells play an important role in innate immune responses to viral infections. Here, we review recent insights into the role of NK cells in viral infections, with particular emphasis on human studies. We first discuss NK cells in the context of acute viral infections, with flavivirus and influenza virus infections as examples. Questions related to activation of NK cells, homing to infected tissues and the role of tissue- resident NK cells in acute viral infections are also addressed. Next, we discuss NK cells in the context of chronic viral infections with hepatitis C virus and HIV-1. Also covered is the role of adaptive- like NK cell expansions as well as the appearance of CD56− NK cells in the course of chronic infection. Specific emphasis is then placed in viral infections in patients with primary immunodeficiencies affecting NK cells. Not least, studies in this area have revealed an important role for NK cells in controlling several herpesvirus infections. Finally, we address new data with respect to the activation of NK cells and NK cell function in humans infected with severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) giving rise to coronavirus disease 2019 (COVID-19). Antibody- dependent Almost 50 years ago, a small number of research groups In humans, mature NK cells are traditionally identified cellular cytotoxicity started to observe unexpected spontaneous cytotoxic as CD3−CD56+ lymphocytes. They were long thought to (ADCC). A mechanism by which activities among lymphocytes. -
Structural Basis of Mouse Cytomegalovirus M152/Gp40 Interaction with Rae1γ Reveals a Paradigm for MHC/MHC Interaction in Immune
Structural basis of mouse cytomegalovirus m152/gp40 PNAS PLUS interaction with RAE1γ reveals a paradigm for MHC/MHC interaction in immune evasion Rui Wanga, Kannan Natarajana, Maria Jamela R. Revillezaa, Lisa F. Boyda, Li Zhia,1, Huaying Zhaob, Howard Robinsonc, and David H. Marguliesa,2 aMolecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; bDynamics of Macromolecular Assembly Section, Laboratory of Cellular Imaging and Macromolecular Biophysics, National Institute of Biomolecular Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892; and cNational Synchrotron Light Source, Brookhaven National Laboratories, Upton, NY 11973 Edited by K. Christopher Garcia, Stanford University, Stanford, CA, and approved October 24, 2012 (received for review August 17, 2012) Natural killer (NK) cells are activated by engagement of the NKG2D NKG2D ligands, we examined the binding of the MCMV m152 receptor with ligands on target cells stressed by infection or glycoprotein to its RAE1 ligands. Our previous studies investigated tumorigenesis. Several human and rodent cytomegalovirus (CMV) the quantitative interaction of m152 with different RAE1 isoforms immunoevasins down-regulate surface expression of NKG2D (21). Here we report the X-ray structure of the complex of m152 ligands. The mouse CMV MHC class I (MHC-I)–like m152/gp40 glyco- with RAE1γ, the confirmation of the intermolecular contacts protein down-regulates retinoic acid early inducible-1 (RAE1) observed in the crystal structure by site-directed mutagenesis and NKG2D ligands as well as host MHC-I. Here we describe the crystal in vitro binding assays, a comparison of the binding of m152 to structure of an m152/RAE1γ complex and confirm the intermolec- RAE1 and of NKG2D to RAE1, and the functional effects of ular contacts by mutagenesis. -
Genitourinary Pathology (Including Renal Tumors)
LABORATORY INVESTIGATION THE BASIC AND TRANSLATIONAL PATHOLOGY RESEARCH JOURNAL LI VOLUME 99 | SUPPLEMENT 1 | MARCH 2019 2019 ABSTRACTS GENITOURINARY PATHOLOGY (INCLUDING RENAL TUMORS) (776-992) MARCH 16-21, 2019 PLATF OR M & 2 01 9 ABSTRACTS P OSTER PRESENTATI ONS EDUCATI ON C O M MITTEE Jason L. Hornick , C h air Ja mes R. Cook R h o n d a K. Y a nti s s, Chair, Abstract Revie w Board S ar a h M. Dr y and Assign ment Co m mittee Willi a m C. F a q ui n Laura W. La mps , Chair, C ME Subco m mittee C ar ol F. F ar v er St e v e n D. Billi n g s , Interactive Microscopy Subco m mittee Y uri F e d ori w Shree G. Shar ma , Infor matics Subco m mittee Meera R. Ha meed R aj a R. S e et h al a , Short Course Coordinator Mi c h ell e S. Hir s c h Il a n W ei nr e b , Subco m mittee for Unique Live Course Offerings Laksh mi Priya Kunju D a vi d B. K a mi n s k y ( Ex- Of ici o) A n n a M ari e M ulli g a n Aleodor ( Doru) Andea Ri s h P ai Zubair Baloch Vi nita Parkas h Olca Bast urk A nil P ar w a ni Gregory R. Bean , Pat h ol o gist-i n- Trai ni n g D e e p a P atil D a ni el J. -
Monoclonal Antibody to CD161 / KLRB1 - Purified
OriGene Technologies, Inc. OriGene Technologies GmbH 9620 Medical Center Drive, Ste 200 Schillerstr. 5 Rockville, MD 20850 32052 Herford UNITED STATES GERMANY Phone: +1-888-267-4436 Phone: +49-5221-34606-0 Fax: +1-301-340-8606 Fax: +49-5221-34606-11 [email protected] [email protected] SM1611PT Monoclonal Antibody to CD161 / KLRB1 - Purified Alternate names: C-type lectin domain family 5 member B, CLEC5B, HNKR-P1a, Killer cell lectin-like receptor subfamily B member 1, NKRP1A, Natural killer cell surface protein P1A Quantity: 25 µg Concentration: 1.0 mg/ml Background: Natural killer (NK) cells are lymphocytes that mediate cytotoxicity and secrete cytokines after immune stimulation. Several genes of the C-type lectin superfamily, including the rodent NKRP1 family of glycoproteins, are expressed by NK cells and may be involved in the regulation of NK cell function. The KLRB1 (CD161) protein contains an extracellular domain with several motifs characteristic of C type lectins, a transmembrane domain, and a cytoplasmic domain. The KLRB1 protein is classified as a type II membrane protein because it has an external C terminus. In mouse the NKRP1 family has three members, NKRP1A, B and C, whilst in human only one member has been identified. The human protein has received the designation CD161, and the mouse proteins have been referred to as CD161a, b and c. Engagement of CD161c has been reported to have activating function in NK cells, whilst engagement of CD161b is inhibitory. CD161 is expressed by almost all NK cells and with a small subset of CD3+ve T cells. -
CD29 Identifies IFN-Γ–Producing Human CD8+ T Cells With
+ CD29 identifies IFN-γ–producing human CD8 T cells with an increased cytotoxic potential Benoît P. Nicoleta,b, Aurélie Guislaina,b, Floris P. J. van Alphenc, Raquel Gomez-Eerlandd, Ton N. M. Schumacherd, Maartje van den Biggelaarc,e, and Monika C. Wolkersa,b,1 aDepartment of Hematopoiesis, Sanquin Research, 1066 CX Amsterdam, The Netherlands; bLandsteiner Laboratory, Oncode Institute, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; cDepartment of Research Facilities, Sanquin Research, 1066 CX Amsterdam, The Netherlands; dDivision of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; and eDepartment of Molecular and Cellular Haemostasis, Sanquin Research, 1066 CX Amsterdam, The Netherlands Edited by Anjana Rao, La Jolla Institute for Allergy and Immunology, La Jolla, CA, and approved February 12, 2020 (received for review August 12, 2019) Cytotoxic CD8+ T cells can effectively kill target cells by producing therefore developed a protocol that allowed for efficient iso- cytokines, chemokines, and granzymes. Expression of these effector lation of RNA and protein from fluorescence-activated cell molecules is however highly divergent, and tools that identify and sorting (FACS)-sorted fixed T cells after intracellular cytokine + preselect CD8 T cells with a cytotoxic expression profile are lacking. staining. With this top-down approach, we performed an un- + Human CD8 T cells can be divided into IFN-γ– and IL-2–producing biased RNA-sequencing (RNA-seq) and mass spectrometry cells. Unbiased transcriptomics and proteomics analysis on cytokine- γ– – + + (MS) analyses on IFN- and IL-2 producing primary human producing fixed CD8 T cells revealed that IL-2 cells produce helper + + + CD8 Tcells. -
KIR Polymorphism Modulates the Size of the Adaptive NK Cell Pool in Human C Ytomegalovirus−Infected Individuals
KIR Polymorphism Modulates the Size of the Adaptive NK Cell Pool in Human C ytomegalovirus−Infected Individuals This information is current as Angela R. Manser, Nadine Scherenschlich, Christine Thöns, of September 26, 2021. Hartmut Hengel, Jörg Timm and Markus Uhrberg J Immunol published online 13 September 2019 http://www.jimmunol.org/content/early/2019/09/12/jimmun ol.1900423 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/09/12/jimmunol.190042 Material 3.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 26, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published September 13, 2019, doi:10.4049/jimmunol.1900423 The Journal of Immunology KIR Polymorphism Modulates the Size of the Adaptive NK Cell Pool in Human Cytomegalovirus–Infected Individuals Angela R. Manser,* Nadine Scherenschlich,* Christine Tho¨ns,† Hartmut Hengel,‡,x Jo¨rg Timm,† and Markus Uhrberg* Acute infection with human CMV (HCMV) induces the development of adaptive NKG2C+ NK cells. -
A New Hope for Cd56negcd16pos NK Cells As Unconventional Cytotoxic Mediators: an Adaptation to Chronic Diseases
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2020 A New Hope for CD56negCD16pos NK Cells as Unconventional Cytotoxic Mediators: An Adaptation to Chronic Diseases Forconi, Catherine S ; Oduor, Cliff I ; Oluoch, Peter O ; Ong’echa, John M ; Münz, Christian ;Bailey, Jeffrey A ; Moormann, Ann M Abstract: Natural Killer (NK) cells play an essential role in antiviral and anti-tumoral immune responses. In peripheral blood, NK cells are commonly classified into two major subsets: CD56brightCD16neg and CD56dimCD16pos despite the characterization of a CD56negCD16pos subset 25 years ago. Since then, several studies have described the prevalence of an CD56negCD16pos NK cell subset in viral non- controllers as the basis for their NK cell dysfunction. However, the mechanistic basis for their cytotoxic impairment is unclear. Recently, using a strict flow cytometry gating strategy to exclude monocytes, we reported an accumulation of CD56negCD16pos NK cells in Plasmodium falciparum malaria-exposed children and pediatric cancer patients diagnosed with endemic Burkitt lymphoma (eBL). Here, we use live-sorted cells, histological staining, bulk RNA-sequencing and flow cytometry to confirm that this CD56negCD16pos NK cell subset has the same morphological features as the other NK cell subsets and a similar transcriptional profile compared to CD56dimCD16pos NK cells with only 120 genes differentially expressed (fold change of 1.5, p < 0.01 and FDR<0.05) out of 9235 transcripts. CD56negCD16pos NK cells have a distinct profile with significantly higher expression of MPEG1 (perforin 2), FCGR3B (CD16b), FCGR2A, and FCGR2B (CD32A and B) as well as CD6, CD84, HLA-DR, LILRB1/2, and PDCD1 (PD-1), whereas Interleukin 18 (IL18) receptor genes (IL18RAP and IL18R1), cytotoxic genes such as KLRF1 (NKp80) and NCR1 (NKp46), and inhibitory HAVCR2 (TIM-3) are significantly down-regulated compared to CD56dimCD16pos NK cells. -
A Novel CD4+ CTL Subtype Characterized by Chemotaxis and Inflammation Is Involved in the Pathogenesis of Graves’ Orbitopa
Cellular & Molecular Immunology www.nature.com/cmi ARTICLE OPEN A novel CD4+ CTL subtype characterized by chemotaxis and inflammation is involved in the pathogenesis of Graves’ orbitopathy Yue Wang1,2,3,4, Ziyi Chen 1, Tingjie Wang1,2, Hui Guo1, Yufeng Liu2,3,5, Ningxin Dang3, Shiqian Hu1, Liping Wu1, Chengsheng Zhang4,6,KaiYe2,3,7 and Bingyin Shi1 Graves’ orbitopathy (GO), the most severe manifestation of Graves’ hyperthyroidism (GH), is an autoimmune-mediated inflammatory disorder, and treatments often exhibit a low efficacy. CD4+ T cells have been reported to play vital roles in GO progression. To explore the pathogenic CD4+ T cell types that drive GO progression, we applied single-cell RNA sequencing (scRNA-Seq), T cell receptor sequencing (TCR-Seq), flow cytometry, immunofluorescence and mixed lymphocyte reaction (MLR) assays to evaluate CD4+ T cells from GO and GH patients. scRNA-Seq revealed the novel GO-specific cell type CD4+ cytotoxic T lymphocytes (CTLs), which are characterized by chemotactic and inflammatory features. The clonal expansion of this CD4+ CTL population, as demonstrated by TCR-Seq, along with their strong cytotoxic response to autoantigens, localization in orbital sites, and potential relationship with disease relapse provide strong evidence for the pathogenic roles of GZMB and IFN-γ-secreting CD4+ CTLs in GO. Therefore, cytotoxic pathways may become potential therapeutic targets for GO. 1234567890();,: Keywords: Graves’ orbitopathy; single-cell RNA sequencing; CD4+ cytotoxic T lymphocytes Cellular & Molecular Immunology