Figure 7.

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.