The Development and Function of CD8+ innate-like lymphocytes

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DESCRIPTION (provided by applicant): Conventional and non-conventional T cells develop in the thymus. Non-conventional T cells that have features typically associated with innate immune cells are termed innate-like lymphocytes (ILLs). We and others have described a population of CD8+ ILLs, characterized by expression of the activation/memory markers CD44 and CD122, expression of the T-box transcription factor Eomesodermin (Eomes) and ability to produce IFN¿ rapidly after ex vivo stimulation. These CD8+ ILLs develop via a cell-extrinsic mechanism mediated by IL-4 production from a population of thymocytes that express promyelocytic leukemia zinc finger protein (PLZF), a known transcriptional regulator of innate cells. This proposal describes a 5-year career development plan and research strategy to develop an independent career as a laboratory-based academic physician scientist. Under the mentorship of Dr. Gary Koretzky, and utilizing the outstanding training environment in the Division of Hematology/Oncology at the University of Pennsylvania, this plan will help the candidate foster the skills needed for her to become an independent investigator evaluating the role of ILLs in the immune responses. The proposed research strategy aims to investigate the novel mechanism of cytokine driven T cell development and to define the function of CD8+ ILLs. Employing complementary in vitro and in vivo strategies, the focus of Aim 1 is to elucidate how Eomes and the IL-4 signaling pathway regulate CD8+ ILL development. There is currently scant data regarding the function of CD8+ ILLs. Therefore, Aim 2 is designed to investigate the role of CD8+ ILLs in response to bacterial and viral pathogens.