Metabolic checkpoint in TH17 cell differentiation

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DESCRIPTION (provided by applicant): Coordination of T cell metabolic programs with cell fate decisions is a fundamental issue in adaptive immunity. Upon antigen stimulation, na¿ve T cells undergo clonal expansion and lineage differentiation to mediate immune effector functions. Concomitantly, T cells exhibit a marked increase of the bioenergetic and biosynthetic demands over the resting state, with a particularly striking increase in glycolysis. The reliance on glycolysis to generate ATP in the presence of oxygen, known as aerobic glycolysis or the Warburg effect, is a hallmark of proliferating T cells (and cancer cells). Indeed, upregulation of metabolism has been proposed to be a necessary step or "checkpoint" to facilitate T cell activation, but how the metabolic pathways intersect with immune signals in T cell fate decisions and autoimmune dysregulation is poorly defined. Among T cell effector populations, TH17 cells play a key pathogenic role in many autoimmune disorders, including multiple sclerosis and its murine model experimental autoimmune encephalomyelitis (EAE). Differentiation of TH17 cells is closely related to the generation of induced regulatory T cells (Treg), and the balance between TH17 and Treg cells is mainly shaped by the cytokine environment. We recently show that TH17 and Treg cells have marked differences in their glycolytic activity and expression of glycolytic enzymes. Hypoxia-inducible factor 1¿ (HIF1¿), a master transcription factor for glycolytic gene expression, is selectively induced in TH17 cells. Deletion of HIF1¿ impairs the expression of glycolytic enzymes and the differentiation of TH17 cells, and ameliorates the pathogenesis of EAE. Our preliminary studies further implicated mTORC1 signaling, an important regulator of cell growth and metabolism, in this process. Moreover, acute deletion of HIF1¿ or pharmacological inhibition of glycolytic pathway after disease onset exerted therapeutic effects on EAE. We hypothesize that the interplay between mTORC1, HIF1¿ (and related transcription factors) and T cell glycolysis orchestrates a metabolic checkpoint for TH17 differentiation and autoimmune diseases. Specifically, we will determine: (1) how glycolysis is regulated by immune signals in TH17 cells; (2) how the glycolytic pathway orchestrates a metabolic checkpoint for TH17 differentiation; (3) whether T cell glycolytic pathway is important for therapeutic targeting of TH17-mediated diseases and for the maintenance of TH17 responses. There has been little description on modulating T cell metabolic pathways for the treatment of autoimmune and inflammatory diseases. Insights gained from this application may significantly impact our understanding of T cell metabolism and TH17 cell biology and manifest legitimate therapeutic opportunities.