Modulating immune responses by shifting the balance of effector versus regulatory/memory T cells has significant potential as therapy for various autoimmune diseases and preventing organ transplant rejection. The mammalian Target Of Rapamycin Complex 1 (mTORC1) has diverse effects in T cells and can function to direct T cell fate. Direct mTORC1 inhibition provides potent immunosuppression but is associated with significant toxicity. Dissecting the mechanisms that account for the multiple mTORC1 effects on T cell differentiation is required to develop targeted therapies that provide desirable immunomodulatory effects without the toxicity associated with rapamycin treatment.
The function of activated T cells is closely linked to their elevated metabolic state. Thus, inhibition of T cell metabolism via disruption of glucose metabolism or amino acid availability can alter T cell function. mTORC1 activity is acutely sensitive to the metabolic cues and has established roles in regulating cellular metabolism in other systems, through the control of Hypoxia Inducible Factor 1α (HIF1α) and Sterol Response Element Binding Protein 1c (Srebp1c) transcriptional activity. Based on the hypothesis that mTORC1 integrates the control of T cell metabolism and differentiation via common pathways, our data reveals a dual role for mTORC1/HIF1α in controlling glucose metabolism and CD8 T cell function. Lipid metabolism, controlled by mTORC1/Srebp1c in other cellular systems, has also been linked to T cell differentiation. Preliminary results demonstrate that activated T cells contain active mTORC1/Srebp1c signaling and suggest mTORC1 activity controls Srebp1c target genes, supporting a potential role for mTORC1/Srebp1c in the control of T cell function. This project aims to characterize the role for mTORC1/Srebp1c in the activation, differentiation and function of T lymphocytes using complementary pharmacological and genetic approaches and using state of the art in vivo technologies.
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