Multiple Sclerosis Relapses Are Associated With EBV-Specific T-Cell Expansion Amid Broad Immune Activation

Background and Objectives Epstein-Barr virus (EBV) infection is strongly implicated in multiple sclerosis (MS), yet the mechanisms linking EBV to disease pathogenesis remain unclear. EBV-specific T cells are hypothesized to contribute to MS through molecular mimicry. We aimed to investigate the relationship between EBV-specific T cells and MS relapses using longitudinal T-cell receptor (TCR) repertoire profiling. Methods We analyzed TCR repertoires from sequential peripheral blood samples collected before and after relapses in 5 patients with MS. CD4 + and CD8 + T cells were sorted into naive, memory, and regulatory subsets. TCR antigen specificity was determined using exact matches to public databases and GLIPH2-based clustering, covering EBV, cytomegalovirus, influenza, Mycobacterium tuberculosis , and self-antigens. The results were compared with those from healthy controls. Results At baseline, patients with MS showed a significant enrichment of EBV-specific TCRs within CD8 + T cells, comparable with patterns seen in other autoimmune diseases. After relapses, EBV-specific TCR frequencies markedly increased across all T-cell subsets. TCRs recognizing other viral antigens, including polyspecific TCRs with broad reactivity, displayed similar baseline enrichment and relapse-associated expansion patterns. Discussion Our findings indicate a temporal association between MS relapses, global immune activation, and EBV-specific T-cell expansions, which is consistent with a two-step model of MS relapse immunopathogenesis. An initial, unidentified trigger induces broad immune activation, promoting the expansion of antiviral T cells, including those specific to EBV. These EBV-specific and polyspecific T cells with heightened cross-reactivity may then contribute to MS relapses. Larger studies are needed to further define the role of T-cell dynamics in MS pathogenesis.