ABSTRACT
Introduction: Epstein-Barr virus (EBV) infection precedes signs of multiple sclerosis (MS) pathology and cross-reactive antibodies might link EBV infection mechanistically to CNS autoimmunity. Objective(s): As an altered immune reaction against EBV antigens in T cells of MS patients has been suggested, we queried deep, peripheral blood T-cell receptor beta chain (TCRbeta) repertoires of 1395 MS patients, 887 controls, and 35 monozygotic, MS-discordant twin pairs for multimerconfirmed, viral antigen-specific TCRbeta sequences. Aim(s): Quantification of HLA-matched EBV-specific, CMV-specific, Influenza A virus-specific, and SARS-CoV-2-specific TCRbeta sequences in MS patients, controls, and COVID-19 patients. Result(s): We detected higher numbers of MHC-I restricted EBVspecific TCRbeta sequences in MS patients, and validated this with independent cohorts and sequencing methods. Genetic as well as early environmental factors could be excluded by validation in diseased siblings of monozygotic twin pairs discordant for MS. Therapeutic blockade of VLA-4-mediated T-cell extravasation amplified this observation, while interferon beta treatment and B-cell depletion did not modulate occurrence of EBV-specific T cells. EBV-specific CD8+ T cells were characterized as effectormemory cells in peripheral blood and cerebrospinal fluid of healthy controls. In MS patients, the cerebrospinal fluid also contained EBV-specific central-memory CD8+ T cells, suggesting recent priming. Conclusion(s): MS is not only preceded by EBV infection, but also associated with a broader EBV-specific TCR repertoire, which would be consistent with an ongoing anti-EBV immune reaction in MS patients.