T cell receptor sequences of myelin-reactive T cells

The autoimmune responses in multiple sclerosis (MS), particularly those mediated by T cells targeting CNS-derived antigens, are broadly recognized. However, the defining triggers underlying these responses remain poorly understood. Epstein-Barr virus (EBV) infection has emerged as a primary risk factor for MS, suggesting a potential role for molecular mimicry in which EBV-specific immune responses cross-react with myelin antigens. In this study, we performed an integrated multi-cohort observational analysis of the T cell receptor (TCR) repertoires of MS patients (n = 129) and controls (n = 94) from public datasets, to explore the relationship between viral- and myelin-specific T cell responses. Our analysis identified clusters of TCRs that were significantly depleted among MS patients, many of which were associated with cytomegalovirus (CMV). By generating a library of myelin-reactive TCRs from myelin peptide-stimulated peripheral blood mononuclear cells (PBMCs) obtained from three MS patients and mapping these sequences to the public TCR repertoire database, we also uncovered a lower frequency of myelin-reactive TCRs in MS samples compared to controls in the public datasets (p < 0.001). In addition, epitope-specificity prediction revealed a broader response to EBV- (p = 0.0046), but not CMV-derived epitopes (p = 0.091) in MS patients. Collectively, these findings underscore the complex role of latent herpesvirus infections in MS. Particularly, they suggest that EBV-specific immune responses may contribute to the dysregulation of the immune system in MS patients, potentially through mechanisms of molecular mimicry. While the broader response to EBV-derived epitopes and the lower frequency of myelin-reactive TCRs in MS samples are both compelling disease-associated signatures and suggest that viral and autoimmune mechanisms may each play a role in MS pathogenesis, they currently represent corollary observations; further functional validation is warranted to determine whether these mechanisms act independently or if interactions between them are essential to drive the disease process.