Dynamics of Myelin-Specific T-Cell Repertoires Mirror Disease Activity and Central Nervous System Trafficking in...

Autoreactive lymphocytes are thought to contribute to tissue injury in the pathogenesis of multiple sclerosis (MS). However, reliable biomarkers reflecting myelin-specific immune responses and disease activity remain limited. In HLA-DRB1*15:01-positive individuals, the myelin basic protein (MBP) epitope MBP85-99 represents a well-characterized immunodominant target of CD4+ T cells. Using classical spectratyping, we characterized the peripheral T-cell receptor (TCR) β-chain repertoire reactive to MBP85-99 in individuals with MS, according to their HLA-DRB1 haplotypes. Selected rearrangements were further evaluated in cerebrospinal fluid (CSF), cytokine-defined T-cell subsets, and longitudinal samples collected during interferon beta-1a treatment. A restricted set of shared ("public") MBP85-99-reactive TCR rearrangements was identified in individuals with MS and differed from the repertoire observed in healthy controls. These TCRs were more frequently detected during periods of active disease than during remission. Two disease-associated public rearrangements were enriched in active MS, whereas one rearrangement was preferentially observed in healthy controls. HLA-DRB1*15:01-restricted MBP85-99-specific public TCR signatures were associated with inflammatory disease activity in MS and may help distinguish pathogenic from non-pathogenic autoreactive responses. In a longitudinal sub-cohort (n = 15, ~10-year follow-up), the RSI of the principal disease-associated rearrangement TRBV19-TRBJ2.4 correlated positively with cumulative relapse burden (Spearman ρ = 0.782, p = 0.002), providing preliminary evidence that these TCR signatures reflect long-term inflammatory disease activity. These findings support further validation of antigen-specific TCR profiling as a biomarker strategy in MS using contemporary high-throughput immune repertoire technologies.