Defective T‐cell control of Epstein–Barr virus infection in multiple sclerosis

• Published in: Clinical & translational immunology Vol. 6; no. 1; pp. e126 - n/a
• Main Authors: Pender, Michael P, Csurhes, Peter A, Burrows, Jacqueline M, Burrows, Scott R
• Format: Journal Article
• Language: English
• Published: Australia Nature Publishing Group 01.01.2017; John Wiley & Sons, Inc
• Subjects: Antigens; CD4 antigen; CD8 antigen; Cytokines; Cytomegalovirus; Cytotoxicity; Epstein-Barr virus; Flow cytometry; Histocompatibility antigen HLA; Immunoglobulin G; Infections; Interferon; Latent infection; Lymphoblastoid cell lines; Lymphocytes; Lymphocytes B; Lymphocytes T; Multiple sclerosis; Original; Peptides; Population; Proteins; Viral infections; Viruses
• ISSN: 2050-0068; 2050-0068
• DOI: 10.1038/cti.2016.87

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. Multiple sclerosis: Faulty immune response to Epstein‐Barr virus Defective immune control of a common virus that causes ‘kissing disease’ might lead to the development of multiple sclerosis (MS). Michael Pender of the Royal Brisbane and Women's Hospital, Scott Burrows of the QIMR Berghofer Medical Research Institute, and colleagues in Australia analysed the response of T cells, a type of immune cell, to Epstein‐Barr virus (EBV) infection in 95 MS patients and in 56 healthy people with latent EBV infection. They found that T cell control of EBV was defective in MS patients. This might be the reason behind the accumulation of EBV‐infected B cells, the immune cells targeted by the virus, in the central nervous system and the subsequent development of MS. Further studies are needed to determine if therapies aimed at controlling EBV infection could prevent or even cure MS.