Mapping of CD8 T-cell recognition to latent EBV infection and neuroantigens reveals HLA-specific depletion of T-cell responses in multiple sclerosis

Multiple sclerosis (MS) is a complex autoimmune disease with an unclear contribution from antigen-specific CD8 T cells. To enumerate adaptive immune responses associated with MS and to identify MS-related epitopes recognized by CD8 T cells, we evaluated T-cell recognition of 1,158 predicted major histocompatibility complex (MHC)-binding peptides derived from latent EBV antigens (laEBVs) and selected neuroantigens (NAgs) using DNA barcode-labelled pMHC multimers. HLA-B*07:02+ individuals living with relapsing-remitting MS (RRMS) and progressive MS (PMS) were characterized by a relative reduction in EBNA6-specific and MAG-specific CD8 T cells compared to healthy donors. Furthermore, both RRMS and PMS patients exhibited a delayed expansion of CMV- and laEBV-specific CD8 T cells compared to healthy donors indicating an age-specific interaction with disease. Female RRMS patients were moreover characterized by a specific reduction of laEBV-specific CD8 T cells compared to male RRMS patients. NAg-specific CD8 T cells recognized heterogeneous peptides, were of low cellular frequency in peripheral blood, and exhibited a circulating, naive-like, anergic phenotype. In contrast, virus-specific CD8 T cells were characterized by high-frequency cellular responses with an effector-like, tissue-homing phenotype. These immunophenotypes were largely shared between MS and healthy donors. Collectively, our data provide novel insights into CD8 T-cell recognition of both NAg and laEBV antigens in MS and constitute a key reference map of epitopes for further immunomonitoring of EBV- and self-specific CD8 T cells in health and disease.