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

## TL;DR

This study identifies CD8+ T cell clonotypes in MS patients that react to Epstein–Barr virus, suggesting a potential role for EBV in MS development.

## Contribution

The study reveals specific CD8+ T cell clonotypes in MS patients with reactivity to EBV antigens, linking EBV to MS immunopathology.

## Key findings

- 23 highly expanded and activated CD8+ T cell clonotypes were identified in MS cerebrospinal fluid.
- Six CD8+ T cell clonotypes recognized EBV antigens and novel mimotopes.
- EBV DNA and transcripts were detected in cerebrospinal fluid of MS patients with EBV-specific CD8+ T cells.

## Abstract

CD8+ T cells are the dominant clonally expanded lymphocyte population in multiple sclerosis (MS) lesions but their clonal identity, function and antigen specificity are not well understood. A comprehensive single-cell RNA-sequencing and T cell receptor-sequencing analysis of the cerebrospinal fluid and blood from individuals in the MS and control cohorts revealed a subset of 23 highly expanded and activated CD8+ T cell clonotypes that were enriched predominantly in the cerebrospinal fluid in the MS cohort. Using unbiased and targeted antigen discovery approaches, six CD8+ T cell clonotypes recognizing Epstein–Barr virus (EBV) antigens and multiple novel mimotopes were identified. Although the majority of mimotopes did not elicit functional responses, three of the expanded CD8+ T cell receptors from patients with MS were reactive to EBV. EBV DNA and transcripts were detected in cerebrospinal fluid, including in patients with MS who had highly expanded EBV-specific CD8+ T cells. These findings shed vital insight into the role of CD8+ T cells in MS and support an important role of EBV in MS immunopathology.

Sabatino and colleagues examine expanded CD8+ T cell clonotypes from a small cohort of multiple sclerosis patients. They identified several cognate peptide epitopes that derive from Epstein–Barr virus, suggesting EBV reactivation may drive pathogenesis in these patients.