DESCRIPTION (provided by the applicant): We have recently uncovered a role for CD8+ T cells in the innate immune response and this proposal is designed to understand the mechanisms by which CD8+ T cells contribute to innate immunity. Specifically, we have shown that a subset of CD8+ T cells rapidly secrete IFN-gamma in response to infection with Listeria monocytogenes (LM). This IFN-? secretion is antigen/TCR independent and is promoted by cytokine stimulation. The specific aims are as follows: I) To characterize the CD8+ T cells that secrete IFN-gamma, II) To determine the contribution of CD8+ T cells in innate immune responses, and III) To use microarray analysis to determine which genes are involved in controlling responsiveness of CD8+ T cells to IL-12 and IL-18. To achieve specific aim I, we will further characterize the cell surface phenotype of the CD8+ T cells secreting IFN-? with regard to their activation/memory status. Furthermore, we will determine the levels of the cytokine receptors responsible for inducing IFN-gamma secretion and see if this correlates with responsiveness. Specific aim II will require in vivo studies to analyze what role CD8+ T cells play in the innate immune response. Once a surface phenotype has been established from specific aim I, we will use this knowledge to transfer purified populations of CD8+ T cells into IFN gamma, knock-out mice to overcome the natural defect in IFN-gamma which results in mortality upon infection with LM. Using microarray analysis for specific aim III will allow us to identify genes which are involved in controlling the responsiveness of CD8+ T cells to innate stimulation mediated by IL-12 and IL-18. The results of the experiments outlined in this proposal will advance our knowledge concerning the role of CD8+ T cells in innate responses to bacteria, viruses and tumors. Armed with this knowledge, we can use these CD8+ T cells to help combat infectious diseases and tumors early in the disease state.
|Effective start/end date||1/04/03 → 31/03/05|