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

项目摘要 不变的自然杀伤T（iNKT）细胞是T淋巴细胞的一个子集，位于边界， 适应性免疫和先天性免疫。它们具有高度限制的T细胞受体（TCR）， 检测由非经典MHC分子CD1d呈递的糖脂抗原， 对抗原或细胞因子的刺激反应迅速。NKT细胞在免疫调节中发挥重要作用。 抗微生物免疫反应，因为它们快速产生多种 细胞因子，它们被认为是癌症和其它疾病的治疗剂。 NKT细胞由于其独特的机制而获得其效应子表型 胸腺中的选择和分化。NKT细胞的效应物命运范围 我们才刚刚开始认识到控制NKT细胞的机制 效应子命运选择完全未知。我们的研究旨在了解 控制iNKT细胞发育的分子机制，重点是E 蛋白质转录因子，它们的抑制剂ID蛋白质，以及它们的下游靶标。 这些蛋白质是iNKT细胞数量和效应细胞命运选择的关键调节剂。 在本授权申请中，我们提出了实验来确定E2A的要求 在iNKT细胞发育中，两种基因的过度表达和表达不足的后果是： 推定的E2A靶基因，Lef1和Bcl 6。我们的研究将对我们的 了解NKT细胞的数量和功能如何调节。此外，我们的研究 将提供深入了解机制，操纵NKT细胞效应命运，从而 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.