HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis
| Autor: | Carolina Cruciani, Yingdong Zhao, Jian Wang, Lena Mühlenbruch, Wolfgang Faigle, William W. Kwok, Mathias Hauri-Hohl, Julie T. Nguyen, Mireia Sospedra, Roland Martin, Christian Münz, Ivan Jelcic, Magdalena Foege, Jar-How Lee, Veronika Haunerdinger, Andreas Lutterotti, Richard Reynolds, Nora C. Toussaint, Thomas Eiermann, Thomas M.C. Binder, Laura Fuentes-Font, Lennart Opitz, Hans-Georg Rammensee, Stefan Stevanovic, Reza Naghavian |
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| Přispěvatelé: | University of Zurich, Martin, Roland |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
CD4-Positive T-Lymphocytes
Male immunopeptidome cross-reactivity Proteome T-Lymphocytes medicine.disease_cause 10263 Institute of Experimental Immunology Cross-reactivity Epitope Monocytes 0302 clinical medicine 11 Medical and Health Sciences Cells Cultured HLA-DR Serological Subtypes 0303 health sciences B-Lymphocytes autoreactive CD4+ Repertoire Middle Aged Female Life Sciences & Biomedicine Akkermansia muciniphila Adult Biochemistry & Molecular Biology Multiple Sclerosis HLA-DR15 molecules T cells 610 Medicine & health autoimmune disease Biology Cross Reactions General Biochemistry Genetics and Molecular Biology Virus Article 03 medical and health sciences Young Adult 1300 General Biochemistry Genetics and Molecular Biology medicine Humans HLA cross-restriction Antigens Alleles 030304 developmental biology Aged Autoimmune disease B cells Science & Technology HLA-DR-derived self-peptides Multiple sclerosis HLA-DR15 Cell Biology 06 Biological Sciences medicine.disease biology.organism_classification 10040 Clinic for Neurology 10036 Medical Clinic Immunology Peptides T cell repertoire Immunologic Memory 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Cell 1281.e20 Cell, 183 (5) |
| ISSN: | 1097-4172 0092-8674 |
| Popis: | Summary 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. Graphical Abstract Highlights • HLA-DR15 present abundant HLA-DR-derived self-peptides on B cells • Autoreactive T cells in MS recognize HLA-DR-derived self-peptides/DR15 complexes • Foreign peptides/DR15 complexes trigger potential autoreactive T cells in MS • HLA-DR15 shape an autoreactive T cell repertoire by cross-reactivity/restriction The immunopeptidome presented by HLA-DR15 molecules links the most important genetic and environmental risk factors for multiple sclerosis, the HLA-DR15 haplotype and Epstein-Barr virus, by shaping a cross-reactive CD4+ T cell repertoire. |
| Databáze: | OpenAIRE |
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