Defective T-cell control of Epstein–Barr virus infection in multiplesclerosis

摘要

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⁺ andCD8⁺ T-cell populations expanded, with increased functionality oflatent-specific CD8⁺ T cells. With increasing disease duration,EBV-specific CD4⁺ and CD8⁺ T cells progressivelydeclined, consistent with T-cell exhaustion. The anti-EBNA1 IgG titre correlatedinversely with the EBV-specific CD8⁺ T-cell frequency. We postulatethat defective CD8⁺ T-cell control of EBV reactivation leads to anexpanded population of latently infected cells, including autoreactive B cells.