Multiple sclerosis-associated HLA demarcates EBV-specific CD8+ T cells with an exhausted and brain residency phenotype

In multiple sclerosis (MS), T cells could contribute to disease in their attempt to control the Epstein-Barr virus (EBV). Here, we compared the presence of HLA-B7 (higher MS risk) or HLA-A2 (lower MS risk) and investigated the effector phenotype of EBV epitope-specific CD8+ T cells in MS using spectral flow cytometry. In contrast to HLA-A2, HLA-B7-restricted CD8+ T cells recognized few EBV epitopes. These HLA-B7-restricted EBV-specific CD8+ T cells expressed CNS residency markers and were most abundant in postmortem CNS compartments of an HLA-A2+B7+ MS donor. HLA-B7-restricted EBV-specific CD8+ T cells displayed a more exhausted phenotype (PD-1+CD244+CD160+KLRG1+TIGIT+). In line with these findings, anti-EBNA1 IgG levels were elevated in patients with MS carrying HLA-B7 but lacking HLA-A2. These data support a model in which the confined response against EBV generates circulating HLA-B7-restricted CD8+ T cells less able to control EBV and more prone to infiltrate the CNS.