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Cellular Immune Response to Chicken Pox (Varicella)
CD4+ and CD8+ T cells play dual roles in varicella-zoster virus (VZV) pathogenesis. The first role is to deliver the virus to cutaneous sites during primary VZV infection, permitting replication at these sites and the successful transmission of the virus to other susceptible individuals. The second contribution of T cells is to provide the critical antigen-specific adaptive immunity needed to stop viral replication and maintain VZV latency in sensory ganglia. The equilibrium between VZV and the host can be predicted to be served by immune evasion mechanisms in at least two important ways, including the facilitation of cell-associated viremia during primary VZV infection and silent persistence in dorsal root ganglia. Interference with antigen presentation by MHC class I downregulation may be expected to play a role in both circumstances. Transient interference with MHC class II expression in varicella skin lesions should facilitate local replication and transmission. In addition, when VZV reactivates, the capacity of viral gene products to block the upregulation of MHC class II expression triggered by interferon-gamma should permit a sufficient period of viral replication to cause the lesions of herpes zoster, despite the presence of VZV-specific T cells, and to allow transmission of the virus to susceptible individuals. Although the effort is at an early stage compared to studies of other viral pathogens, identifying the VZV gene products that exert these effects and their mechanisms of interference has the potential to reveal novel aspects of MHC class I and class II antigen processing and presentation.
Natural varicella-zoster virus (VZV) infection and immunization with live attenuated varicella vaccine elicits T lymphocytes that recognize VZV glycoproteins, gpI-V, and the immediate early/tegument protein, the product of gene 62 (IE62). Proliferation or cytotoxicity assays, done under limiting dilution conditions to estimate responder cell frequencies, indicate no preferential recognition of VZV proteins by human T cells. Analysis of the primary cytotoxic T lymphocyte (CTL) response after vaccination demonstrates that both gpI and IE62 are targets of the early response. CD4(+)- and CD8(+)-mediated CTL recognition of these viral proteins can be detected with natural and vaccine-induced immunity. Responder cell frequencies for protein-specific T cell proliferation and CTL function are generally comparable in subjects with natural and vaccine-acquired immunity to VZV. Exogenous reexposure to VZV results in enhanced T cell proliferation and may be an important mechanism for maintaining virus-specific cellular immunity. Providing exogenous reexposure by giving varicella vaccine to individuals who have preexisting natural immunity markedly increases the responder cell frequencies of T cells that proliferate in response to VZV antigen and the numbers of circulating CTL that recognize VZV proteins.
Varicella immunization provided the opportunity to examine the kinetics of interleukin (IL)-10, IL-12 and interferon (IFN)-gamma production elicited during primary in vivo sensitization with proteins of varicella-zoster virus (VZV), a common human herpesvirus. VZV-specific IFN-gamma release and T cell proliferation were elicited by immunization and persisted through 15 months of follow-up. The induction of VZV-specific T cells and IgG antibodies was accompanied by transient increases in IL-10 and IL-12 production. T cell proliferation to VZV was significantly lower in adults at 15 months than in vaccinated children or naturally immune subjects and correlated with lower IFN-gamma responses in individual vaccinees. After primary immunity was induced, continued IL-12 production was not necessary to maintain the predominant Th1-type response elicited by VZV. Cytokine profiles observed during primary in vivo sensitization to VZV suggest that parallel increases in IFN-gamma and IL-10 may be important in the induction of immunity to some viral pathogens.
Cell-mediated immunity to VZV was detected in 87% of children and 94% of adults at 5 years.