E and Id protein function in natural killer T cell differentiation

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DESCRIPTION (provided by applicant): Natural killer (NK) T cells are a subset of lymphocytes that play an important role in the response to M. tuberculosis and in preventing autoimmune disease and cancer but their inappropriate activation can lead to diseases such as atherosclerosis, allergy or asthma. NKT cells recognize glycolipid antigen presented on CD1d through their T cell receptor but they also express activating receptors commonly associated with NK cells, and they exist in an primed state allowing them to produce copious amounts of cytokine rapidly after encounter with antigen. NKT cells acquire this effector phenotype as a consequence of their unique mechanism of selection and differentiation in the thymus. However, the range of effector fates that NKT cells can acquire is only beginning to be appreciated and the mechanisms controlling NKT cell effector fate choice is completely unknown. My research is directed at understanding the molecular mechanisms that control development of adaptive and innate lymphocytes with a focus on the E protein basic helix-loop-helix (bHLH) transcription factors and their antagonists the Id proteins. These proteins are critical regulators of lymphocyte development and in the NKT cell lineage we hypothesize that these bHLH proteins control both positive selection of NKT cells and their choice of effector cell fate. In this grant application w propose to determine: 1) the range of NKT cell effector fates controlled by bHLH proteins and 2) the role of E protein dose in selection of the E protein target genes that drive these effector fat choices. Our studies will have a major impact on our understanding of how NKT cells function and how their development and effector states are controlled. In addition, our studies will provide insight into mechanisms to manipulate NKT cell effector fate and thereby alter immune responses at their inception.