Mechanisms of E protein transcription factor-dependent iNKT cell expansion and differentiation

项目摘要 不变自然杀伤T细胞(INKT)是位于交界处的T淋巴细胞亚群 适应性免疫和先天免疫。它们具有高度受限的T细胞受体(TCR)， 检测非经典MHC分子CD1d提呈的糖脂抗原 对抗原或细胞因子刺激反应迅速。NKT细胞在 抗微生物免疫反应和由于其快速产生多个 细胞因子，它们被认为是癌症和其他疾病的治疗剂。 NKT细胞因其独特的机制而获得其效应表型 在胸腺中的选择和分化。效应器范围决定NKT细胞的命运 Can Acquired才刚刚开始被认识，但控制NKT细胞的机制 效应器的命运选择是完全未知的。我们的研究旨在了解 控制iNKT细胞发育的分子机制 蛋白质转录因子及其抑制物ID蛋白及其下游靶标。 这些蛋白是iNKT细胞数量和效应细胞命运选择的关键调节因子。 在这项拨款申请中，我们建议进行实验，以确定E2A的需求 在iNKT细胞发育中，两个基因的过度和低表达的后果 可能的E2a靶基因，Lef1和Bcl6。我们的学习将对我们的 了解NKT细胞的数量和功能是如何调节的。另外，我们的研究 将提供对操纵NKT细胞效应器命运的机制的见解，从而 在一开始就改变免疫反应。

Project Summary Invariant natural killer T (iNKT) cells are a subset of T lymphocytes that sit at the boarder of adaptive and innate immunity. They have highly restricted T cell receptors (TCRs) that detect glycolipid antigen presented by the non-classical MHC molecule CD1d and they respond rapidly to antigen or cytokine stimulation. NKT cells play an important role in anti-microbial immune responses and because of their rapid production of multiple cytokines they are being considered as therapeutic agents in cancer and other diseases. NKT cells acquire their effector phenotype as a consequence of their unique mechanism of selection and differentiation in the thymus. The range of effector fates that NKT cells can acquire is only beginning to be appreciated but the mechanisms controlling NKT cell effector fate choice are completely unknown. Our research is directed at understanding the molecular mechanisms that control iNKT cell development with a focus on the E protein transcription factors, their inhibitors the ID proteins, and their downstream targets. These proteins are critical regulators of iNKT cell numbers and effector cell fate choice. In this grant application we propose experiments to determine the requirements for E2A in iNKT cell development an the consequences of over- and under-expression of two putative E2A target genes, Lef1 and Bcl6. Our studies will have a major impact on our understanding of how NKT cell number and function is regulated. In addition, our studies will provide insight into mechanisms to manipulate NKT cell effector fate and thereby alter immune responses at their inception.