Cross talk between innate and adaptive immunity in viral and intracellular bacterial infection.

摘要

Typically, host immune responses are classified into two arms: innate and adaptive immunity. Innate immunity induces a wide variety of mechanisms including complement activation and interferon (IFN) signaling. Adaptive immunity depends on specialized population of antigen-specific lymphocytes, the B and T lymphocytes. In this thesis proposal, I have investigated the role of complement and double-stranded RNA-dependent interferon inducible protein kinase, PKR, in regulating antigen-specific T cell responses to acute viral and intracellular bacterial infections.;In specific aim 1, I examined the role of complement component 3 (C3) in regulating CD8+ and CD4+ T cell activation during infection of mice with an intracellular bacteria, Listeria monocytogenes (LM). My studies showed that C3 promotes activation and expansion of CD4+ and CD8+ T cells in LM-infected mice. Additionally, I present evidence that C3-dependent expansion of T cells does not require C5a, a downstream effector of complement.;In specific aim 2, I examined the role of several possible mechanisms of complement dependent CD8+ T cell regulation including complement receptor 3 (CR3), antibodies/B cells, IL-4, and C5a in lymphocytic choriomeningitis virus (LCMV) infection. My studies indicated that C3 promotes T cell responses to LCMV by mechanisms independent of CR3, C5a, B cells, or IL-4.;In LCMV infection, type I IFNs (IFN-I) play a critical role in controlling early viral replication and enhancing the primary virus-specific CD8 + T cell response to LCMV. IFNs induce the antiviral effects through transcriptional upregulation of IFN-stimulated genes (ISGs), which include PKR. I determined the role of PKR and IFN-I in regulating CD8 + T cells and viral control during primary and secondary LCMV infections (specific aim 3). My studies provided strong evidence that IFN-I and PKR are required for optimal viral control during primary and secondary T cell responses to LCMV, regardless of the magnitude of the virus-specific CD8+ T cell response. Moreover, we found that the requirement for PKR is pathogen dependent, because IFN-I but not PKR is required to control of vaccinia virus (VV) during a secondary response. These findings have implications not only in understanding viral pathogenesis but also in development of effective vaccines against viral infections.