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HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis.

  • Wang J Neuroimmunology and MS Research, Neurology Clinic, University Hospital Zurich, University of Zurich, Zurich 8091, Switzerland.
  • Jelcic I Neuroimmunology and MS Research, Neurology Clinic, University Hospital Zurich, University of Zurich, Zurich 8091, Switzerland.
  • Mühlenbruch L Department of Immunology, Institute of Cell Biology, University of Tübingen, Tübingen 72076, Germany; German Cancer Consortium (DKTK), Partner Site Tübingen, Tübingen 72076, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen 72076, Germany.
  • Haunerdinger V Pediatric Stem Cell Transplantation, University Children's Hospital Zurich, Zurich 8032, Switzerland.
  • Toussaint NC NEXUS Personalized Health Technologies, ETH Zurich, Zurich 8093, Switzerland; Swiss Institute of Bioinformatics, Zurich, Switzerland.
  • Zhao Y Biometric Research Program, Division of Cancer Treatment and Diagnosis, NCI, NIH, Rockville, MD 20850, USA.
  • Cruciani C Neuroimmunology and MS Research, Neurology Clinic, University Hospital Zurich, University of Zurich, Zurich 8091, Switzerland.
  • Faigle W Neuroimmunology and MS Research, Neurology Clinic, University Hospital Zurich, University of Zurich, Zurich 8091, Switzerland.
  • Naghavian R Neuroimmunology and MS Research, Neurology Clinic, University Hospital Zurich, University of Zurich, Zurich 8091, Switzerland.
  • Foege M Neuroimmunology and MS Research, Neurology Clinic, University Hospital Zurich, University of Zurich, Zurich 8091, Switzerland.
  • Binder TMC HLA Laboratory of the Stefan Morsch Foundation (SMS), Birkenfeld 55765, Germany.
  • Eiermann T Department of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany.
  • Opitz L Functional Genomics Center Zurich, Swiss Federal Institute of Technology and University of Zurich, Zurich 8057, Switzerland.
  • Fuentes-Font L Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK.
  • Reynolds R Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK.
  • Kwok WW Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
  • Nguyen JT One Lambda, Inc., a part of Transplant Diagnostics Thermo Fisher Scientific, 22801 Roscoe Blvd., West Hills, CA 91304, USA.
  • Lee JH One Lambda, Inc., a part of Transplant Diagnostics Thermo Fisher Scientific, 22801 Roscoe Blvd., West Hills, CA 91304, USA.
  • Lutterotti A Neuroimmunology and MS Research, Neurology Clinic, University Hospital Zurich, University of Zurich, Zurich 8091, Switzerland.
  • Münz C Viral Immunobiology, Institute of Experimental Immunology, University of Zurich, Zurich 8057, Switzerland.
  • Rammensee HG Department of Immunology, Institute of Cell Biology, University of Tübingen, Tübingen 72076, Germany; German Cancer Consortium (DKTK), Partner Site Tübingen, Tübingen 72076, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen 72076, Germany.
  • Hauri-Hohl M Pediatric Stem Cell Transplantation, University Children's Hospital Zurich, Zurich 8032, Switzerland.
  • Sospedra M Neuroimmunology and MS Research, Neurology Clinic, University Hospital Zurich, University of Zurich, Zurich 8091, Switzerland.
  • Stevanovic S Department of Immunology, Institute of Cell Biology, University of Tübingen, Tübingen 72076, Germany; German Cancer Consortium (DKTK), Partner Site Tübingen, Tübingen 72076, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen 72076, Germany.
  • Martin R Neuroimmunology and MS Research, Neurology Clinic, University Hospital Zurich, University of Zurich, Zurich 8091, Switzerland. Electronic address: roland.martin@usz.ch.
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  • 2020-10-22
Published in:
  • Cell. - 2020
B cells
HLA cross-restriction
HLA-DR-derived self-peptides
HLA-DR15 molecules
T cell repertoire
T cells
autoimmune disease
autoreactive CD4+
cross-reactivity
immunopeptidome
multiple sclerosis
English The HLA-DR15 haplotype is the strongest genetic risk factor for multiple sclerosis (MS), but our understanding of how it contributes to MS is limited. Because autoreactive CD4+ T cells and B cells as antigen-presenting cells are involved in MS pathogenesis, we characterized the immunopeptidomes of the two HLA-DR15 allomorphs DR2a and DR2b of human primary B cells and monocytes, thymus, and MS brain tissue. Self-peptides from HLA-DR molecules, particularly from DR2a and DR2b themselves, are abundant on B cells and thymic antigen-presenting cells. Furthermore, we identified autoreactive CD4+ T cell clones that can cross-react with HLA-DR-derived self-peptides (HLA-DR-SPs), peptides from MS-associated foreign agents (Epstein-Barr virus and Akkermansia muciniphila), and autoantigens presented by DR2a and DR2b. Thus, both HLA-DR15 allomorphs jointly shape an autoreactive T cell repertoire by serving as antigen-presenting structures and epitope sources and by presenting the same foreign peptides and autoantigens to autoreactive CD4+ T cells in MS.
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  • English
Open access status
hybrid
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Persistent URL
https://folia.unifr.ch/global/documents/262561
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