Regulatory T cells (Tregs) are central mediators of immune tolerance, but can also be a major hurdle to tumor immunity and immunotherapy. Tregs respond to TCR stimulation in the periphery and develop into activated Tregs (aTregs), whose function is important for tissue homeostasis in non-lymphoid organs and immune regulation in the tumor microenvironment. In addition to TCRs, microenvironment-derived signals, especially nutrients, have emerged as important regulators of T cell activation and differentiation, although the functional importance of nutrients in Tregs and whether and how they signal are unclear. We have a long-standing interest in understanding mTORC1 signaling in adaptive immunity and Treg biology. Our previous work has centered upon understanding the immune functions of mTORC1. How upstream signals regulate mTORC1 to shape Treg activation programs and tissue and tumor-specific responses remain poorly understood and will be the focus of this renewal application. To this end, we performed an unbiased, genome-wide screen for regulators of mTORC1 in Tregs, and identified the small G proteins RagA and Rheb1 among the top-ranking positive regulators of mTORC1 activity. Treg-specific deletion of RagA led to mild TH1-associated autoimmune responses, while loss of both RagA and the partially-redundant RagB resulted in the development of a fatal, Scurfy-like inflammatory disorder. Mechanistically, we found that RagA/B linked amino acids to mTORC1 activation and the generation of aTregs. Furthermore, we identified the functional importance of Rheb1 and its homolog Rheb2 in aTreg generation, and the interplay of RagA/B with Rheb and lysosomal signaling. We hypothesize that amino acids signal via RagA/B and interplay with Rheb and lysosomal signaling to license mTORC1 activation for functional programming of aTreg generation and suppressive activity.
Aim 1. Establish the effects and mechanisms of RagA/B signaling in aTreg generation and function.
Aim 2. Identify the integration of amino acid signals by TSC?Rheb and RagA/B in Tregs.
Aim 3. Define lysosomal signaling and reconstruct mTORC1 signaling circuits in Tregs. We predict our studies will establish a new paradigm in Treg biology and mechanisms of mTORC1 regulation, with the potential to translate into innovative strategies to target cancer and other diseases.
Statement Regulatory T cells (Tregs) are indispensable for the establishment of immune tolerance and the prevention of autoimmune diseases, but also serve as a major obstacle to tumor immunity and immunotherapy. In addition to T cell receptors, microenvironment-derived signals, especially nutrients, have emerged as important regulators of T cell activation and differentiation, although the functional importance of nutrients in Tregs and whether and how they signal are unclear. Hence, a better understanding of nutrient sensing and signaling mechanisms in Tregs is essential for our efforts to prevent and treat autoimmune diseases and cancer.
