Regulation of Natural Killer T cell lineage diversification by the Src-like Adaptor protein 2

 描述（由申请人提供）：衔接蛋白在受体信号传导中起关键作用。尽管它们缺乏酶活性，但这些蛋白质具有能够与其他蛋白质相互作用并形成信号传导复合物的模块化结构域，从而导致蛋白质的激活或降解。 信号级联的抑制。Src样衔接蛋白（SRAP和SLAP 2）构成了一个蛋白质家族，在多种细胞类型中表达，但在淋巴细胞中研究最广泛。迄今为止，没有在T淋巴细胞的体内功能已归因于SLAP 2。我们已经鉴定出SLAP 2是控制“先天”T淋巴细胞群体（不变自然杀伤T（iNKT）细胞）的发育和功能的必需分子。虽然数量较低，但这些iNKT细胞在免疫学上很重要，并参与调节与广泛疾病相关的多种免疫应答，包括自身免疫和过敏，以及感染性疾病，癌症和代谢。我们建议表征iNKT细胞中SLAP 2缺陷的表型、功能和分子后果。提出的实验不仅将提供对iNKT细胞发育和功能的更全面的理解，而且这项研究将有助于确定使iNKT细胞的一个子集的发育偏离另一个子集的方法，并有效地治疗由iNKT细胞引起和/或调节的疾病。为了利用这些先天性T细胞的免疫潜能，重要的是要充分了解它们的功能和发育

 DESCRIPTION (provided by applicant): Adaptor proteins play a crucial role in receptor signaling. Even though they lack enzymatic activity, these proteins have modular domains that are able to interact with other proteins and form signaling complexes, leading to the activation or inhibition of signaling cascades. Src-like adapter proteins (SLAP and SLAP2) constitute a family of proteins that are expressed in a variety of cell types but are studied most extensively in lymphocytes. To date, no in vivo function in T lymphocytes has been ascribed to SLAP2. We have identified SLAP2 as an essential molecule controlling the development and function of a population of "innate" T lymphocytes, the Invariant Natural Killer T (iNKT) cells. While numerically low, these iNKT cells are immunologically important and have been implicated in regulating a multitude of immune responses associated with a broad range of diseases, including autoimmunity and allergy but also infectious diseases, cancer and metabolism. We propose to characterize the phenotypic, functional and molecular consequences of SLAP2-deficiency in iNKT cells. Not only will the proposed experiments provide a more comprehensive understanding of iNKT cell development and function, but this research will help identify ways to skew the development of one subset of iNKT cells over another and effectively treat diseases caused and/or modulated by iNKT cells. In order to harness the immunotherapeutic potential of these innate T cells, it is important to gain a full appreciation of their function and development