HLA-B7–Restricted EBV-Specific CD8+ T Cells Are Dysregulated in Multiple Sclerosis

Abstract

It was hypothesized that the EBV-specific CD8+ T cell response may be dysregulated in multiple sclerosis (MS) patients, possibly leading to a suboptimal control of this virus. To examine the CD8+ T cell response in greater detail, we analyzed the HLA-A2–, HLA-B7–, and HLA-B8–restricted EBV- and CMV-specific CD8+ T cell responses in a high number of MS patients and control subjects using tetramers. Content in cytolytic granules, as well as cytotoxic activity, of EBV- and CMV-specific CD8+ T cells was assessed. We found that MS patients had a lower or a higher prevalence of HLA-A2 and HLA-B7, respectively. Using HLA class I tetramers in HLA-B7+ MS patients, there was a higher prevalence of MS patients with HLA-B*0702/EBVRPP-specific CD8+ T cells ex vivo. However, the magnitude of the HLA-B*0702/EBVRPP-specific and HLA-B*0702/CMVTPR-specific CD8+ T cell response (i.e., the percentage of tetramer+ CD8+ T cells in a study subject harboring CD8+ T cells specific for the given epitope) was lower in MS patients. No differences were found using other tetramers. After stimulation with the HLA-B*0702/EBVRPP peptide, the production of IL-2, perforin, and granzyme B and the cytotoxicity of HLA-B*0702/EBVRPP-specific CD8+ T cells were decreased. Altogether, our findings suggest that the HLA-B*0702–restricted viral (in particular the EBV one)-specific CD8+ T cell response is dysregulated in MS patients. This observation is particularly interesting knowing that the HLA-B7 allele is more frequently expressed in MS patients and considering that EBV is associated with MS.