A central role for mTOR in Determining T Cell Activation versus Tolerance

 描述（由申请人提供）：在该提案的前5年期间，我们已经能够确定mTOR在调节T细胞活化、分化和功能中的核心作用。我们的研究已经导致了一种新的范式的发展，其中mTOR整合来自免疫微环境的信号来调节TCR识别的结果。T细胞中mTOR的选择性缺失防止了在正常活化条件下Th 1、Th 2、Th 17效应T细胞的产生。相比之下，我们的研究揭示了在不存在mTOR活性的情况下抗原识别的默认结果是Foxp 3+调节性T细胞的默认结果。mTOR通过两种复合物进行信号传导：mTOR复合物I（mTORC 1），其由小GTdR Rheb激活并含有接头蛋白Raptor;以及mTORC 2，其含有接头Rictor。我们通过产生Rheb-/- T细胞选择性地删除mTORC 1活性。这些细胞不能分化为Th 1和Th 17细胞，但容易成为Th 2细胞。或者，Rictor-/- T细胞容易分化成Th 1和Th 17细胞，但不能成为T2细胞。此外，我们已经能够证明AGC激酶血清和糖皮质激素调节激酶1（SGK 1）是mTORC 2的下游靶点，其增强Th 2分化将抑制Th 1分化。与此同时，我们的研究表明，mTORC 1是必要的CD 8+效应T细胞的产生和功能，而mTORC 2的抑制选择性增强CD 8+记忆T细胞的产生。在本提案中，我们试图进一步了解mTOR调节TCR参与结果的机制：在目标1中，我们将定义mTORC 1和mTORC 2协调代谢和T细胞分化和功能的机制。具体来说，我们将定义不同的 Th 1和Th 2细胞的代谢程序。在这样做的过程中，我们将揭示加塔-3的新的代谢功能以及核糖核蛋白YB-1调节T细胞功能的新作用。在目标2中，我们将证明SGK 1通过Foxo 1的选择性磷酸化在调节CD 8+记忆T细胞发育中的作用。在目的3中，我们将检验TCR诱导的亮氨酸内流导致mTOR通过Ragulator复合物募集到内体的假设。此外，我们将测试的假设，这些信号成分的不对称分配可以促进产生2个子细胞具有不同的表型和代谢特性。总的来说，通过研究mTOR信号传导的下游分子，我们希望确定治疗自身免疫性疾病、预防移植排斥反应、增强疫苗和对感染性疾病和肿瘤的免疫力的新靶点。

 DESCRIPTION (provided by applicant): During the first 5 years of this proposal, we have been able to define a central role for mTOR in regulating T cell activation, differentiation and function. Our studies have led to the development of a novel paradigm whereby mTOR integrates signals from the immune microenvironment to regulate the outcome of TCR recognition. Selective deletion of mTOR in T cells prevents the generation of Th1, Th2, Th17 effector T cells under normally activating conditions. In contrast, our studies reveal that the default outcome for antigen recognition in the absence of mTOR activity is to that of Foxp3+ regulatory T cells. mTOR signals via two complexes: mTOR Complex I (mTORC1) which is activated by the small GTPase Rheb and contains the adaptor protein Raptor and mTORC2 which contains the adaptor Rictor. We selectively deleted mTORC1 activity by creating Rheb-/- T cells. Such cells failed to differentiate into Th1 and Th17 cells but readily become Th2 cells. Alternatively, Rictor-/- T cells readily differentiate into Th1 and Th17 cells but fail to become T2 cells. Additionally, we have been able to show that the AGC kinase Serum- and glucocorticoid-regulated kinase 1 (SGK1) is a downstream target of mTORC2 that reciprocally enhances Th2 differentiation will inhibiting Th1 differentiation. In parallel, our studies have revealed that mTORC1 is necessary for CD8+ effector T cell generation and function, while the inhibition of mTORC2 selectively enhances the generation of CD8+ memory T cells. In this proposal we seek to further understand the mechanisms by which mTOR regulates the outcome of TCR engagement: In Aim 1 We will define the mechanisms by which mTORC1 and mTORC2 coordinate metabolism and T cell differentiation and function. Specifically we will define distinct metabolic programs from Th1 and Th2 cells. In doing so we will reveal novel metabolic functions for GATA-3 as well as a novel role for regulating T cell function for the ribonucleoprotein YB-1. In Aim 2 we will demonstrate a role for SGK1 in regulating CD8+ memory T cell development through the selective phosphorylation of Foxo1. In Aim 3 We will test the hypothesis that TCR-induced influx of leucine leads to the recruitment of mTOR to the endosome by the Ragulator complex. Furthermore, we will test the hypothesis that the asymmetric partitioning of these signaling components can promote the generation of 2 daughter cells with distinct phenotypic and metabolic properties. Overall, by studying the molecules downstream of mTOR signaling we hope to identify novel targets for treating autoimmune disease, preventing transplantation rejection and enhance vaccines and immunity to infectious diseases and tumors.