Immunology. doi: 10.1111/imm.12808. [Epub ahead of print]
Growing evidence points to a deregulated response to Epstein-Barr virus (EBV) in the CNS of patients with Multiple Sclerosis (pwMS) as a possible cause of disease. In this study, we have investigated the response of a subpopulation of effector CD8+ T cells to EBV in 36 healthy donors and in 35 pwMS in active and inactive disease. We have measured the expression of markers of degranulation, the release of cytokines, cytotoxicity and the regulation of effector functions by inhibitory receptors, such as programmed death-1 (PD-1) and human inhibitor receptor Ig-like transcript 2 (ILT2). We demonstrate that polyfunctional cytotoxic CD8+CD57+ T cells are able to kill EBV-infected cells in healthy donors. In contrast, an anergic exhaustion-like phenotype of CD8+CD57+ T cells with high expression of PD-1 was observed in inactive pwMS compared with active pwMS or healthy donors. Detection of CD8+CD57+ T cells in meningeal inflammatory infiltrates from post-mortem MS tissue confirmed the association of this cell phenotype with the disease pathological process. The overall results suggest that ineffective immune control of EBV in pwMS during remission may be one factor preceding and enabling the reactivation of the virus in the CNS and may cause exacerbation of the disease.