Broader Epstein–Barr virus–specific T cell receptor repertoire in patients with multiple sclerosis

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.

Epstein-Barr Virus-Induced Genes and Endogenous Retroviruses in Immortalized B Cells from Patients with Multiple Sclerosis

“…Recently, cross-reactive antibodies against EBNA-1 and the glial antigen GlialCAM have been found in the CSF of individuals with MS [ 69 ]. In addition, the EBV-specific T cell repertoire in individuals with MS seems to be expanded [ 70 ], and EBV-specific CD8-positive T-cells are frequently observed in the CSF and in brain tissue at sites of white matter lesions and the meninges in MS [ 71 , 72 ]. These observations suggest ongoing EBV (re-)activation that might challenge the immune homeostasis directly or by transactivation of HERVs.…”

CD8+ T cell clonotypes from prior SARS-CoV-2 infection predominate during the cellular immune response to mRNA vaccination

“…One TCR assigned to Epstein-Barr virus (EBV) matched a TRBV, TRBJ, CDR3, and participant HLA allele to a clonotype signi cantly expanded after dose 2. This is not unexpected, as EBVspeci c T cells have been detected in several pathophysiologic states, though their signi cance is unknown [56][57][58] .…”

Epstein-Barr virus promotes T cell dysregulation in a humanized mouse model of multiple sclerosis

“…The increased brain infiltration in HuPBMC EAE mice may also aid in the study of MS pathology. Though EBV induced immunomodulation of T cell responses is a possible mechanism for inciting MS, it is also possible that immunomodulation occurs alongside additional virus-specific mechanisms, such as infection and immortalization of autoreactive B cells, ineffective or abherent immune control of EBV reactivation, and structural mimicry of CNS antigens by viral proteins (Lang et al ., 2002; Pender, 2003; Laurence and Benito-León, 2017; Lanz et al ., 2022; Schneider-Hohendorf et al ., 2022). An important next step is to assess clinical outcomes and T cell inflammation in the model when engrafted with PBMCs derived from donors with other autoimmune disorders, especially those also linked to EBV infection, such as systemic lupus erythematosus and rheumatoid arthritis (Balandraud and Roudier, 2018; Jog and James, 2021), to determine the generalizability of T cell immunomodulation by EBV in autoimmune susceptibility.…”