Regulation of NKT cell development and function by c-Myb

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DESCRIPTION (provided by applicant): NKT cells represent a distinct subset of T lymphocytes that recognize glycolipid antigens presented by the nonclassical MHC class I molecule CD1d. Antigen recognition by NKT cells results in a "cytokine storm"; the secretion, within hours, of large quantities of Th1 and Th2 cytokines and chemokines, reminiscent of innate rather than adaptive functions. Through this cytokine and chemokine production, NKT cells influence the behavior of many other cells in the immune system, including NK cells, macrophages, other 12 T cells, dendritic cells and neutrophiles, and have been implicated in multiple processes, including microbial immunity, and tumor rejection. Similarly, they seem to play a role in the pathogenesis of autoimmune processes, atherosclerosis and allergy. Our results demonstrate that c-Myb, a transcription factor that plays multiple roles in hematopoiesis, is a critical player in NKT cell development. Inducible deletion of c-Myb in DP thymocytes results in a complete blockade in NKT cell development, previous to positive selection. Preliminary evidence suggests that different mechanisms may be responsible for this effect. c-Myb: thymocytes have a shortened half-life, have defects in TcR1 rearrangement -that may be secondary to the defect in half-life- and have defects in the expression of members of the SLAM/SAP signaling pathway, which is required for NKT cell positive selection. In aim one of this grant we propose experiments to analyze in detail the contributions of these mechanisms to the final phenotype of c-Myb: thymocytes. In aim two we will delete c-Myb from mature NKT cells and analyze its contribution to mature NKT cell homeostasis and function. PUBLIC HEALTH RELEVANCE: NKT cells are a distinct subset of lymphocytes that play an important role in immune responses against pathogens. Alterations in their function may play a role in the pathogenesis of autoimmune disorders such as lupus or diabetes, as well as in atherosclerosis. This project will analyze the role of c-Myb, a transcription factor, in the development and function of NKT cells. A better understanding of these processes may offer clues to their manipulation during disease.