Cytotoxic CD8+ T lymphocytes are the major effector cells of immune system that kill virally infected and cancerous cells. We recently discovered a novel role of interleukin-17A (IL-17A) in promoting cytotoxicity of CD8+ T cells in a mouse model of West Nile virus (WNV) infection. Specifically, we found that 1) cytotoxicity of CD8+ T cells isolated from WNV-infected IL-17A deficient (Il17a-/-) mice is much lower than those from wild- type control mice, resulting in increased viral burden in the brain and higher death rate of Il17a-/- mice; and 2) injection of recombinant mouse IL-17A (rIL-17A) into wild-type mice as late as on day 6 post WNV infection increases the expression of the CD8+ T cell cytotoxic mediator genes (perforin, granzyme and fas-l), which profoundly reduces the viral burden in the brain and increases the survival, suggesting a therapeutic role of IL- 17A in treating WNV infection. In addition, our recent RNA sequencing (RNA-seq) results indicate that IL- 17A may facilitate CD8+ T cell effector functions through activating mammalian target of rapamycin (mTOR) kinase signaling pathway. In this proposal, we will address two key questions: 1) does IL-17A signaling directly act on CD8+ T cells in promoting their cytotoxicity during WNV infection? and 2) what are the key molecular and cellular mechanisms by which IL-17A enhances CD8+ T cell cytotoxicity? Addressing these questions will expand our current knowledge of biological functions of IL-17A and CD8+ T cells, and may also open new opportunities for the development of therapeutic strategies against WNV infection, other viral infections, and even cancer by enhancing IL-17A-mediated CD8+ T cell cytotoxicity.
West Nile virus has killed more than 1,500 and sickened more than 50,000 Americans since 1999, yet no vaccine or specific treatment is available for human use. This proposal characterizes a novel function of interleukin 17A in promoting CD8 T cell cytotoxicity against West Nile virus infection. This research will increase knowledge about biological defense mechanisms, and facilitate the development of therapeutics against West Nile virus infection, other viral infections, and even cancer by enhancing IL-17A-mediated CD8 T cell cytotoxicity.