Clin Transl Immunology. 2017;6(1):e126.
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.
- The T-cell response to EBV-infected B cells is reduced at all stages of MS except during clinical attacks
- The T-cell response to EBV-infected B cells progressively decreases with increasing duration of MS.
These results are consistent with progressive T-cell exhaustion of EBV-specific CD4+ T cells and CD8+ T cells during the course of MS although they could also be due to other factors, for example an age-related decline in the tendency of EBV to reactivate.
The CD8+ T-cell response to EBV lytic phase antigens is reduced at the onset of MS and throughout its course
CD8+ T cells recognizing EBV latent phase antigens in MS show T-cell exhaustion##
Proposed model of defective CD8+ T-cell control of EBV infection in MS. In healthy EBV carriers, (a) there is a dynamic equilibrium between the EBV-infected cell populations and the T-cell response. EBV-specific CD8+ T cells (T cell) exert a key role in controlling EBV infection by killing infected cells in the B blast, germinal centre (GC) B cell, plasma cell and tonsil epithelial cell, but not memory B cell, populations. The large arrows indicate the cycle of EBV infection: virion→B blast→GC B cell→memory B cell→plasma cell→virion→epithelial cell→virion→B blast. Smaller arrows indicate stimulation of T cells by EBV antigens from the infected populations. The relative sizes of the different EBV-infected cell populations are indicated by the circle sizes, based on the study by Hawkins et al.6 The relative sizes of the EBV-specific CD8+ T-cell populations are also indicated by the circle sizes; however, it is important to note that the EBV-specific CD8+ T-cell population is several orders of magnitude larger than the EBV-infected cell population, a distinction not depicted here. For simplicity, the EBV-specific CD4+ T-cell population and anti-EBV antibody response are not shown. At all stages of MS (b–d) the EBV-lytic-specific CD8+ T-cell population is decreased, allowing increased production of virions which infect naive B cells driving them into the blast phase. The resultant expansion of the infected blast population stimulates EBV-latent-specific CD8+ T cells which proliferate and restrict this expansion, but not without increased flow out of infected blast cells into a consequently enlarged EBV-infected GC cell population, which in turn is partially controlled by the augmented EBV-latent-specific CD8+ T-cell population. In the same way the EBV-infected memory B cell pool also grows, as does the population of plasma cells reactivating EBV infection. During clinical attacks of MS (c) there is increased differentiation of EBV-infected memory B cells into lytically infected plasma cells as a result of the various microbial infections that trigger attacks of MS. This EBV reactivation is inadequately regulated by the already deficient EBV-lytic-specific CD8+ T-cell response, resulting in increased virion production and increased infection of the blast pool, this in turn stimulating proliferation of the EBV-latent-specific CD8+ T-cell population which restricts further growth of the infected blast population. In progressive MS (d) the EBV-latent-specific CD8+ T-cell response becomes exhausted (indicated by fading), resulting in unchecked expansion of the infected GC population and the development of EBV-infected lymphoid tissue in the CNS.
we have shown that patients with MS have defective T-cell control of EBV infection which might underlie the accumulation of EBV-infected B cells in the CNS and subsequent development of the disease. We have proposed a model where decreased CD8+ T-cell control of EBV reactivation permits increased production of virus and consequent expansion of the latently infected B-cell population.
To test this model they suggest that further studies are necessary to determine:
(i) the cause of CD8+ EM/EMRA T-cell deficiency in MS, whether it genetically determined, and related to decreased type I IFN production;
(ii) whether CD8+ T-cell deficiency precedes the onset of MS and is present in healthy first-degree relatives of people with MS,
(iii) whether sunlight deprivation and vitamin D deficiency aggravate the CD8+ T-cell deficiency
(iv) how and why the EBV-specific CD4+ T-cell response declines during the course of MS;
(v) whether oral shedding of EBV is increased during clinical attacks;
(vi) whether the frequency of EBV-infected memory B cells in the blood is increased in MS, as in rheumatoid arthritis and systemic lupus erythematosus;
(vii) whether EBV-infected B cells and plasma cells in the CNS in MS are autoreactive, and (viii) finally and most importantly, whether therapies aimed at controlling EBV infection, such as EBV-specific T-cell therapy,prevent and cure MS.