Inflammatory immune responses are regulated by T cell subsets that secrete specific panels of cytokines. While CD8+ T cells that secrete IFN-γ and cytotoxic molecules (Tc1 cells) are known to mediate antiviral immunity, IL-17-secreting CD8+ T (Tc17) cells have only recently been described and the development and function of these cells has not been clearly examined. Using in vitro T cell cultures and mice deficient in transcription factors regulating lineage development, we defined Tc17 development and function. Similar to IL-17 secretion from CD4 T cells, IL-17 secretion from Tc17 cells is dependent on the transcription factor Stat3 and inhibited by Stat1. Expression of transcription factors important for Tc1 function, T-bet and Eomesodermin (Eomes), is reduced in Tc17 cells and consistent with this, Tc17 cells are non-cytotoxic in vitro. However, Tc17 cells are unstable and switch to cytotoxic IFN-γ producing cells when exposed to a Tc1 inducing cytokine, IL-12. Overexpression of the lineage promoting transcription factors T-bet and Eomes is unable to induce a Tc1 phenotype in Tc17 cells and Stat3 is also unable to switch Tc1 cells into Tc17 cells, suggesting additional signals are involved in CD8 T cell lineage commitment. In vivo, Tc17 cells are induced by vaccinia virus, dependant on Stat3, and are capable of mediating antiviral immunity. Tc17 cells acquire an IFN-γ-secreting phenotype after encounter with virus in vivo, however, viral clearance by Tc17 cells is independent of IFN-γ. Instead, viral clearance is correlated with a gain in T-bet expression and cytotoxic function in Tc17 cells which have encountered virus. The development of anti-viral activity independent of IFN-γ, suggests that Tc17 cells may mediate anti-viral immunity through novel mechanisms that depend on the ability of Tc17 cells to acquire other phenotypes.
|Advisor:||Kaplan, Mark H.|
|Commitee:||Dent, Alexander L., Nakshatri, Harikrishna, Wilkes, David S.|
|Department:||Microbiology & Immunology|
|School Location:||United States -- Indiana|
|Source:||DAI-B 72/06, Dissertation Abstracts International|
|Subjects:||Molecular biology, Virology, Immunology|
|Keywords:||CD8 T cells, Cytotoxic t lymphocyte, Il-17, Stat3, Tc17, Th17, Vaccinia virus|
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