Antigen specificity of clonally-enriched CD8+ T cells in multiple sclerosis

CD8+ T cells are the dominant lymphocyte population in multiple sclerosis (MS) lesions where they are highly clonally expanded. The clonal identity, function, and antigen specificity of CD8+ T cells in MS are not well understood. Here we report a comprehensive single-cell RNA-seq and T cell receptor (TCR)-seq analysis of the cerebrospinal fluid (CSF) and blood from a cohort of treatment-naïve MS patients and control participants. A small subset of highly expanded and activated CD8+ T cells were enriched in the CSF in MS that displayed high activation, cytotoxicity and tissue-homing transcriptional profiles. Using a combination of unbiased and targeted antigen discovery approaches, MS-derived CD8+ T cell clonotypes recognizing Epstein-Barr virus (EBV) antigens and multiple novel mimotopes were identified. No CD8+ T cell cross-reactivity was found between the EBV epitopes and self-antigens, but EBV DNA was detected in CSF, including in the same individuals with highly expanded CD8+ T cells. These findings shed vital insight into the role of CD8+ T cells in MS and lend further support an important role of EBV in MS immunopathology. Overall design: Cross-sectional single-cell sequencing analysis of blood and CSF from a cohort of MS patients and control subjects