Mij
Senior Member (Voting Rights)
Abstract
Multiple sclerosis (MS) is strongly linked to Epstein-Barr Virus (EBV) infection, yet how antiviral immunity contributes to disease pathogenesis remains unclear. Here we delineate EBV-specific CD8+ T cell responses at antigen and single cell resolution in treatment-naïve people with MS. This analysis reveals selective expansion of CD8+ T cells directed to EBV-encoded latent antigens, including EBNA3A and EBNA1.
These antigen-specific T cells display enhanced cytotoxicity, a distinct T cell receptor repertoire, and upon engagement with autologous EBV-transformed B cells, adopt a type I interferon-dominated transcriptional state. Most importantly, these MS-specific transcriptional signatures exhibit shared genetic architecture with MS susceptibility genes, supported by enrichment in MS GWAS signals and brain-derived eQTL datasets.
Our findings reframe EBV-specific immunity in MS as a state of antigen-specific dysregulation, implicating aberrant surveillance of latently infected B cells as a central pathogenic mechanism and propose latent EBV-specific CD8⁺ T cells as targets for therapeutic intervention.
Study
Multiple sclerosis (MS) is strongly linked to Epstein-Barr Virus (EBV) infection, yet how antiviral immunity contributes to disease pathogenesis remains unclear. Here we delineate EBV-specific CD8+ T cell responses at antigen and single cell resolution in treatment-naïve people with MS. This analysis reveals selective expansion of CD8+ T cells directed to EBV-encoded latent antigens, including EBNA3A and EBNA1.
These antigen-specific T cells display enhanced cytotoxicity, a distinct T cell receptor repertoire, and upon engagement with autologous EBV-transformed B cells, adopt a type I interferon-dominated transcriptional state. Most importantly, these MS-specific transcriptional signatures exhibit shared genetic architecture with MS susceptibility genes, supported by enrichment in MS GWAS signals and brain-derived eQTL datasets.
Our findings reframe EBV-specific immunity in MS as a state of antigen-specific dysregulation, implicating aberrant surveillance of latently infected B cells as a central pathogenic mechanism and propose latent EBV-specific CD8⁺ T cells as targets for therapeutic intervention.
Study