title: Defective T-cell control of Epstein-Barr virus infection in multiple sclerosis.
abstract: 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+and CD8+T-cell populations expanded, with increased functionality of latent-specific CD8+T cells. With increasing disease duration, EBV-specific CD4+and CD8+T cells progressively declined, consistent with T-cell exhaustion. The anti-EBNA1 IgG titre correlated inversely with the EBV-specific CD8+T-cell frequency. We postulate that defective CD8+T-cell control of EBV reactivation leads to an expanded population of latently infected cells, including autoreactive B cells.
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, Queensland, Australia; Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; Cellular ImmunoIogy Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Pender
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, Queensland, Australia; Cellular ImmunoIogy Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; The University of Queensland Centre for Clinical Research, Brisbane, Queensland, Australia.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Csurhes
authors.affiliation: Cellular ImmunoIogy Laboratory, QIMR Berghofer Medical Research Institute , Brisbane, Queensland, Australia.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Burrows
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, Queensland, Australia; Cellular ImmunoIogy Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burrows