CD4+Foxp3+ regulatory T (Treg) cells play a pivotal role in the control of immunological self-tolerance; yet, excessive Treg cell activities impede immune responses to pathogens and tumors. Following antigen stimulation, resting Treg (rTreg) cells are converted to activated Treg (aTreg) cells, lack of which results in rampant autoimmunity. Nevertheless, how T cell receptor (TCR) signaling promotes aTreg cell generation is poorly understood. Mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and proliferation by integrating signals of growth factors and nutrients. TCR-induced Akt and Erk signaling pathways phosphorylate and inactive the TSC complex, a GTPase activating protein for the lysosomal mTORC1 activator Rheb. As TCR proximal signaling is dynamically regulated, how intermittent TCR signaling propagates to induce sustained mTORC1 signaling has been enigmatic. Notably, recent studies have revealed that TCR signaling induces delayed but persistent expression of amino acid transporters, and amino acid uptake promotes mTORC1 signaling. Our preliminary studies have revealed that amino acid-induced mTORC1 signaling in Treg cells is dependent on the lysosomal Rag family of small GTPases, and Treg cell- specific deletion of RagA and RagB depletes aTreg cells resulting in an early lethal phenotype in mice. Furthermore, we have recently shown that mTORC1 repression under the condition of amino acid starvation is dependent on the Sestrin family of guanine nucleotide inhibitors for RagA/B and the scaffold molecule Szt2 that recruits Sestrins to the lysosome. Based on these observations, we hypothesize that robust mTORC1 signaling in Treg cells is enabled by amino acid-induced activation of Rag family of GTPases, and the nutrient sensing pathway is tuned to modulate aTreg cell generation and function in health and diseases. To test this hypothesis, we will first explore whether diminished Rag GTPase-dependent mTORC1 signaling represses aTreg cell responses in the steady state, and in models of chronic infection and cancer. We will also investigate whether blockade of the TSC pathway corrects the aTreg cell defects and autoimmune phenotypes in mice with reduced Rag GTPase activities to test the assumption that robust nutrient sensing responses compensate for transient TCR-triggered inactivation of the TSC complex to promote mTORC1 signaling in Treg cells. Secondly, we will determine whether enhanced Rag GTPase-dependent mTORC1 signaling promotes aTreg cell responses in models of colitis and adjuvant-induced autoimmunity. We will also explore how amino acid deficiency is sensed to repress mTORC1 signaling. Successful completion of the project will not only reveal the coordination between nutrients and growth factors in Treg cell regulation, but also unravel new strategies of Treg cell targeting to rectify faulty immune responses.
Regulatory T (Treg) cells are an immunosuppressive T cell population with a central role in the control of immune tolerance to healthy tissues and commensals, while excessive Treg cell activities impede immune responses to pathogens and tumors. Experiments proposed in this project will define a role of the nutrient- sensing pathway in the generation and function of Treg cells, which will be instrumental towards targeting these cells for therapy of a number of immunological disorders.
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