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

• Published in: Cell Vol. 183; no. 5; pp. 1264 - 1281.e20
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25-11-2020; Cell Press
• Subjects: Adult; Aged; Alleles; Antigens - immunology; autoimmune disease; autoreactive CD4; B cells; B-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - immunology; Cells, Cultured; Cross Reactions - immunology; cross-reactivity; Female; HLA cross-restriction; HLA-DR Serological Subtypes - immunology; HLA-DR-derived self-peptides; HLA-DR15 molecules; Humans; Immunologic Memory; immunopeptidome; Male; Middle Aged; Monocytes - immunology; multiple sclerosis; Multiple Sclerosis - immunology; Peptides - immunology; Proteome - metabolism; T cell repertoire; T cells; T-Lymphocytes - immunology; Young Adult; autoreactive CD4; multiple sclerosis; T cell repertoire; immunopeptidome; HLA cross-restriction; cross-reactivity; HLA-DR15 molecules; B cells; T cells; autoimmune disease; HLA-DR-derived self-peptides
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2020.09.054

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.
[Display omitted]
•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.