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.
During the first 5 years of this proposal, we have identified a novel and central role for mTOR in regulating T cell activation, differentiation and function. In this proposal, we seek to further understand the mechanisms by which mTOR regulates the outcome of TCR engagement. 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.
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