Role of IL-17-secreting T cells in anti-viral immunity

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Description: This application will evaluate the role of T cell secreting the pro-inflammatory cytokine IL-17 in virus infections. The IL-17-producing T cells may function to protect from infection or may mediate inflammation and immunopathology. IFN is known to promote the development of Th1/Tc1 cells while it inhibits the formation of IL-17 producing T cells. The vaccinia virus model will be investigated. The hypothesis is that vaccinia virus may promote the generation of IL-17-producing T cells because: (1) vaccinia virus drives the production of cytokines important for the differentiation of IL-17-producing T cells (IL-6, TGFbeta1, TNFalpha); and (2) vaccinia virus encodes immunomodulatory proteins that block IFN action (which inhibits the generation of IL-17-producing T cells). Two specific aims are proposed: (1) Define the transcription factors that contribute to the differentiation of IL-17-producting T cells and the production of specific cytokines by these cells. Combination of cells from mice deficient in signal transducer and activator of transcription (STAT3), STAT4 or T-bet and the treatment in culture with different cytokines will be employed. (2) To investigate the function of IL-17-producing T cells in mice infected with vaccinia virus, characterizing deficient mice with altered development of IL-17-producing T cells, the effect of adoptive transfer of IL-17-producing cells and the neutralization of IL-17 with antiserum. These studies may help the development of improved vaccinia virus vaccines which may regulate the formation of IL-17-producing T cells and reduce the damaging inflammation caused by the smallpox vaccine. These investigations will define the role of IL-17-producing T cells in virus infections.