Defective T‐cell control of Epstein–Barr virus infection in multiple sclerosis

Abstract

Mounting evidence indicates that infection with Epstein–Barr virus (EBV) has a major role in the pathogenesis of multiple sclerosis (MS). Defective elimination of EBV-infected B cells by CD8+ T cells might cause MS by allowing EBV-infected autoreactive B cells to accumulate in the brain. Here we undertake a comprehensive analysis of the T-cell response to EBV in MS, using flow cytometry and intracellular IFN-γ staining to measure T-cell responses to EBV-infected autologous lymphoblastoid cell lines and pools of human leukocyte antigen (HLA)-class-I-restricted peptides from EBV lytic or latent proteins and cytomegalovirus (CMV), in 95 patients and 56 EBV-seropositive healthy subjects. In 20 HLA-A2+ healthy subjects and 20 HLA-A2+ patients we also analysed CD8+ T cells specific for individual peptides, measured by binding to HLA-peptide complexes and production of IFN-γ, TNF-α and IL-2. We found a decreased CD8+ T-cell response to EBV lytic, but not CMV lytic, antigens at the onset of MS and at all subsequent disease stages. CD8+ T cells directed against EBV latent antigens were increased but had reduced cytokine polyfunctionality indicating T-cell exhaustion. During attacks the EBV-specific CD4+ and CD8+ T-cell populations expanded, with increased functionality of latent-specific CD8+ T cells. With increasing disease duration, EBV-specific CD4+ and CD8+ T cells progressively declined, consistent with T-cell exhaustion. The anti-EBNA1 IgG titre correlated inversely with the EBV-specific CD8+ T-cell frequency. We postulate that defective CD8+ T-cell control of EBV reactivation leads to an expanded population of latently infected cells, including autoreactive B cells.

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

“…In the 1980s, largely driven by the increasing use of experimental autoimmune encephalomyelitis (EAE) as an animal model of MS, there was a more T cell-centric view of MS pathophysiology. Currently MS disease pathology is thought to invoke key interactions between T and B cells, particularly between their memory subsets, all supported by convergence of clinical trial results and laboratory-based studies [6][7][8][9][10]18,25,52,86]. The high tropism that EBV has for B cells, and its mechanisms of immune avoidance, serve to promote long-term survival and persistence (of both the virus and memory B cells), which fundamentally alter B cell biology, resulting in persistence and accumulation of disease-relevant EBV-infected autoreactive B cells.…”

“…MS does not develop in the absence of exposure to EBV, and EBV is a 'required', but insufficient on its own, contributor in early disease pathophysiology. Independent support comes from an observed higher rate of EBV activation in MS [22,23], a role for EBV in triggering new relapses consistent with a reduced ability of EBV-specific CD8 + T cells (e.g., T cell exhaustion, see Glossary) to limit EBV reactivation in MS patients [24,25], and a strong correlation between the presence of anti-EBV antibodies in blood and disease onset [26][27][28][29]. Evidence of CNS involvement comes from reports of elevated anti-EBNA1 IgG serology associated with the appearance of new gadolinium (Gd)enhancing brain lesions [30] and the presence, in patients, of EBNA1-specific T cells recognizing myelin [31].…”

“…According to the autoreactive B cell hypothesis, defective elimination of EBV-infected B cells by cytotoxic CD8 + T cells results in the accumulation of EBV-infected autoreactive B cells in lymphoid structures and target organs implicated in MS ( Figure 1) [13,25,50]. EBV infection and reactivation are normally controlled by functional EBV-specific cytotoxic CD8 + T cells.…”

Mapping the effects of vitamin D in multiple sclerosis

“…In our exploratory studies, however, we did not find evidence for antigen-specific targeting of EBV by vitamin D. We did not find an increase in the proportion of EBV specific CD8 + T cells, which have recently shown to be functionally impaired in MS [526] , nor a decrease in the EBV load in peripheral blood mononuclear cells in the vitamin D supplemented group, and therefore no evidence for a better elimination of EBV. However, we should bear in mind that we explored this in small sample sizes and only had excess to cells from the circulation in this study.…”

High diversity, turnover, and structural constraints characterize TCR α and β repertoire selection

“…Defective CD8 T-cell control of EBV reactivation may also result in the expansion of EBV-infected, autoreactive B cells in multiple sclerosis (MS) 8 ; improvement of MS has followed infusion of autologous EBV-specific CD8 T-cells 2 . Improved T-cell therapies would benefit from insights derived from approaches that integrate computational biology and structural modeling to predict optimum TCR features and identify TCR antigen-specificity groups [9][10][11][12][13][14] .…”