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

项目概要 不变自然杀伤 T (iNKT) 细胞是位于边界的 T 淋巴细胞的一个子集 适应性和先天免疫。它们具有高度受限的 T 细胞受体 (TCR) 检测由非经典 MHC 分子 CD1d 呈递的糖脂抗原，它们 对抗原或细胞因子刺激做出快速反应。 NKT细胞在以下方面发挥着重要作用 抗微生物免疫反应，并且由于它们快速产生多种 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效应表型 胸腺中的选择和分化。 NKT 细胞的效应命运范围 NKT细胞的控制机制才刚刚开始被人们所认识 效应器命运选择完全未知。我们的研究旨在了解 控制 iNKT 细胞发育的分子机制，重点关注 E 蛋白质转录因子、其抑制剂、ID 蛋白质及其下游靶标。 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因子。 在此拨款申请中，我们提出实验来确定 E2A 的要求 在 iNKT 细胞发育中，两种过度表达和表达不足的后果 推定的 E2A 靶基因 Lef1 和 Bcl6。我们的研究将对我们产生重大影响 了解 NKT 细胞数量和功能如何调节。此外，我们的研究 将深入了解操纵 NKT 细胞效应器命运的机制，从而 从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.