E and Id protein function in natural killer T cell differentiation

描述(申请人提供)：自然杀伤(NK)T细胞是淋巴细胞的一个亚群，在对结核分枝杆菌的反应和预防自身免疫性疾病和癌症方面发挥重要作用，但它们的不适当激活可导致动脉粥样硬化、过敏或哮喘等疾病。NKT细胞通过其T细胞受体识别CD1d上的糖脂抗原，但它们也表达通常与NK细胞相关的激活受体，并以启动状态存在，使其在遇到抗原后迅速产生大量细胞因子。NKT细胞之所以获得这种效应表型，是因为它们在胸腺中选择和分化的独特机制。然而，NKT细胞可以获得的效应命运的范围才刚刚开始被认识，控制NKT细胞效应命运选择的机制完全未知。我的研究旨在了解控制适应性和先天淋巴细胞发育的分子机制，重点是E蛋白碱性螺旋-环-螺旋转录因子及其拮抗剂ID蛋白。这些蛋白质是淋巴细胞的关键调节因子。 在NKT细胞的发育和谱系中，我们假设这些bHLH蛋白既控制着NKT细胞的阳性选择，也控制着它们对效应细胞命运的选择。在这项拨款申请中，我们建议确定：1)由bHLH蛋白控制的NKT细胞效应命运的范围；2)E蛋白剂量在选择E蛋白靶基因中的作用，这些基因驱动这些效应脂肪的选择。我们的研究将对我们理解NKT细胞的功能以及它们的发育和效应状态如何控制产生重大影响。此外，我们的研究将提供对操纵NKT细胞效应器命运的机制的洞察，从而在其开始时改变免疫反应。

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.