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

Area of Science:

• Immunology
• Neuroimmunology
• Genetics

Background:

• The HLA-DR15 haplotype is the primary genetic risk factor for multiple sclerosis (MS).
• The precise mechanisms by which HLA-DR15 contributes to MS pathogenesis remain incompletely understood.
• Autoreactive CD4+ T cells and B cells acting as antigen-presenting cells are implicated in MS.

Purpose of the Study:

• To characterize the immunopeptidomes of HLA-DR15 allomorphs DR2a and DR2b.
• To investigate the role of HLA-DR15 in presenting self-peptides and foreign antigens to autoreactive T cells in MS.

Main Methods:

• Analysis of immunopeptidomes from primary human B cells, monocytes, thymus, and MS brain tissue.
• Characterization of autoreactive CD4+ T cell clones.
• Identification of self-peptides derived from HLA-DR molecules (HLA-DR-SPs).

Main Results:

• Self-peptides from HLA-DR molecules, including DR2a and DR2b, were abundant on B cells and thymic antigen-presenting cells.
• Autoreactive CD4+ T cell clones cross-reacted with HLA-DR-SPs.
• These T cell clones also recognized peptides from Epstein-Barr virus and Akkermansia muciniphila, as well as autoantigens presented by DR2a and DR2b.

Conclusions:

• Both HLA-DR15 allomorphs (DR2a and DR2b) contribute to shaping the autoreactive T cell repertoire in MS.
• HLA-DR15 acts as both an antigen-presenting structure and an epitope source.
• The presentation of shared foreign peptides and autoantigens by HLA-DR15 to autoreactive T cells is a key mechanism in MS pathogenesis.