Broader Epstein–Barr virus–specific T cell receptor repertoire in patients with multiple sclerosis
Tilman Schneider‐Hohendorf, Lisa Ann Gerdes, Béatrice Pignolet, Rachel M. Gittelman, Patrick Ostkamp, Florian Rubelt, Catarina Raposo, Björn Tackenberg, Marianne Riepenhausen, Claudia Janoschka, Christian Wünsch, Florence Bucciarelli, Andrea Flierl‐Hecht, Eduardo Beltrán, Tania Kümpfel, Katja Anslinger, Catharina C. Groß, Heidi Chapman, Ian M. Kaplan, David Brassat, Hartmut Wekerle, Martin Kerschensteiner, Luisa Klotz, Jan D. Lünemann, Reinhard Hohlfeld, Roland Liblau, Heinz Wiendl, Nicholas Schwab
Abstract
Epstein-Barr virus (EBV) infection precedes multiple sclerosis (MS) pathology and cross-reactive antibodies might link EBV infection to CNS autoimmunity. As an altered anti-EBV T cell reaction was suggested in MS, we queried peripheral blood T cell receptor β chain (TCRβ) repertoires of 1,395 MS patients, 887 controls, and 35 monozygotic, MS-discordant twin pairs for multimer-confirmed, viral antigen-specific TCRβ sequences. We detected more MHC-I-restricted EBV-specific TCRβ sequences in MS patients. Differences in genetics or upbringing could be excluded by validation in monozygotic twin pairs discordant for MS. Anti-VLA-4 treatment amplified this observation, while interferon β- or anti-CD20 treatment did not modulate EBV-specific T cell occurrence. In healthy individuals, EBV-specific CD8+ T cells were of an effector-memory phenotype in peripheral blood and cerebrospinal fluid. In MS patients, cerebrospinal fluid also contained EBV-specific central-memory CD8+ T cells, suggesting recent priming. Therefore, MS is not only preceded by EBV infection, but also associated with broader EBV-specific TCR repertoires, consistent with an ongoing anti-EBV immune reaction in MS.