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

Cell. 2020 Nov 25;183(5):1264-1281.e20. doi: 10.1016/j.cell.2020.09.054. Epub 2020 Oct 21.


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.

Keywords: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Antigens / immunology
  • B-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • Cells, Cultured
  • Cross Reactions / immunology
  • Female
  • HLA-DR Serological Subtypes / immunology*
  • Humans
  • Immunologic Memory
  • Male
  • Middle Aged
  • Monocytes / immunology
  • Multiple Sclerosis / immunology*
  • Peptides / immunology
  • Proteome / metabolism
  • T-Lymphocytes / immunology*
  • Young Adult


  • Antigens
  • HLA-DR Serological Subtypes
  • HLA-DR15 antigen
  • Peptides
  • Proteome