Altered CD8+ T cell responses to selected Epstein–Barr virus immunodominant epitopes in patients with multiple sclerosis

Abstract

SUMMARYAn increased frequency of antiviral CD8 + T cells is seen in chronic viral infections. During herpes virus infections the expanded CD8 + T cells are thought to control the reactivation of the latent infection. Because multiple sclerosis (MS), a presumed autoimmune disease of the central nervous system, has been associated with a late Epstein-Barr virus (EBV) infection, we wished to examine whether the CD8 + T cell response to EBV epitopes differed between MS patients and healthy controls. Here we report an increased frequency of CD8 + T cells responding to EBV epitopes from nuclear antigen 3 A (HLA-A2/CLG) and latent membrane protein 2 (HLA-B7/RPP) in MS patients. Noticeably, the altered CD8 + T cell response occurred to some but not all EBV epitopes and did not reach the high level seen during acute infection. The responses towards two immunodominant epitopes from human cytomegalovirus (HCMV) were similar in MS patients and normal controls. Together, our data demonstrate the presence of an increased frequency of CD8 + T cells reacting with two epitopes from EBV in patients with MS. The altered response to only two of the tested EBV epitopes would be consistent with the presence of cross-reactive epitopes.

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

“…With regard to the environmental factors, sero-epidemiological studies revealed that the g-herpesvirus EBV was associated with MS (5,6). We and other investigators demonstrated that EBV-specific cellular immune responses are increased not only in the blood (7)(8)(9)(10) but also in the cerebrospinal fluid of MS patients (11). Interestingly, we showed that the increase in EBV-specific CD8 + T cell response was maximal at disease onset but decreased with disease duration (9).…”

“…However, the magnitude of the CD8 + T cell response in MS patients is significantly lower for the HLA-B7/CMV TPR epitope and tends to be lower for the HLA-B7/ EBV RPP epitope. With regard to the CD8 + T cell responses against the latter, other investigators found either no difference between MS patients and control subjects (37) or an increased magnitude of HLA-B7/EBV RPP -specific CD8 + T cells in MS patients (8), as reflected by the secretion of IFN-g in an ELISPOT assay. However, a direct comparison is difficult, because the data on the magnitude of tetramer + cells were obtained by gating on CD3 + and CD8 + T cells, whereas the ELISPOT assays were performed on total unfractionated PBMC.…”

Intrathecal immune responses to EBV in early MS

“…Among the latter, the g-herpesvirus EBV has been repeatedly associated with this disease [2][3][4]. Large seroepidemiological studies [5][6][7][8] and cellular immune response assessments [9][10][11][12] have demonstrated enhanced EBV-specific immune responses in the blood of MS patients.…”

Epstein-Barr Virus and Autoimmunity

“…One possible mechanism for this is decreased MHC class I expression on B cells, which has been reported to occur in patients with MS [36] and other autoimmune diseases [37], although it remains unclear whether the reported decrease is sufficient to cause decreased EBV-specific CD8+ T-cell cytotoxicity. A recent study found an increased frequency of CD8+ T cells responding to two immunodominant EBV epitopes in MS patients but it was not determined whether these T cells were cytotoxic [38]. EBV-specific CD8+ T cells are enriched in MS brain lesions compared to the peripheral blood, but such enrichment is also found for EBV-specific and cytomegalovirus-specific CD8+ T cells in other inflammatory lesions of the brain and other organs, including non-autoimmune inflammatory lesions [39].…”