HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis
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HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis. / Wang, Jian; Jelcic, Ivan; Mühlenbruch, Lena; Haunerdinger, Veronika; Toussaint, Nora C; Zhao, Yingdong; Cruciani, Carolina; Faigle, Wolfgang; Naghavian, Reza; Foege, Magdalena; Binder, Thomas M C; Eiermann, Thomas; Opitz, Lennart; Fuentes-Font, Laura; Reynolds, Richard; Kwok, William W; Nguyen, Julie T; Lee, Jar-How; Lutterotti, Andreas; Münz, Christian; Rammensee, Hans-Georg; Hauri-Hohl, Mathias; Sospedra, Mireia; Stevanovic, Stefan; Martin, Roland.
in: CELL, Jahrgang 183, Nr. 5, 25.11.2020, S. 1264-1281.e20.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis
AU - Wang, Jian
AU - Jelcic, Ivan
AU - Mühlenbruch, Lena
AU - Haunerdinger, Veronika
AU - Toussaint, Nora C
AU - Zhao, Yingdong
AU - Cruciani, Carolina
AU - Faigle, Wolfgang
AU - Naghavian, Reza
AU - Foege, Magdalena
AU - Binder, Thomas M C
AU - Eiermann, Thomas
AU - Opitz, Lennart
AU - Fuentes-Font, Laura
AU - Reynolds, Richard
AU - Kwok, William W
AU - Nguyen, Julie T
AU - Lee, Jar-How
AU - Lutterotti, Andreas
AU - Münz, Christian
AU - Rammensee, Hans-Georg
AU - Hauri-Hohl, Mathias
AU - Sospedra, Mireia
AU - Stevanovic, Stefan
AU - Martin, Roland
N1 - Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2020/11/25
Y1 - 2020/11/25
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Alleles
KW - Antigens/immunology
KW - B-Lymphocytes/immunology
KW - CD4-Positive T-Lymphocytes/immunology
KW - Cells, Cultured
KW - Cross Reactions/immunology
KW - Female
KW - HLA-DR Serological Subtypes/immunology
KW - Humans
KW - Immunologic Memory
KW - Male
KW - Middle Aged
KW - Monocytes/immunology
KW - Multiple Sclerosis/immunology
KW - Peptides/immunology
KW - Proteome/metabolism
KW - T-Lymphocytes/immunology
KW - Young Adult
U2 - 10.1016/j.cell.2020.09.054
DO - 10.1016/j.cell.2020.09.054
M3 - SCORING: Journal article
C2 - 33091337
VL - 183
SP - 1264-1281.e20
JO - CELL
JF - CELL
SN - 0092-8674
IS - 5
ER -