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.
Lineage commitment and fate determination are fundamental processes in a variety of biological systems. In the immune system, dysregulation of T cell differentiation is the cause of many autoimmune disorders. TH17 cells, a recently identified lineage of effector T cells, play a key role in the pathogenesis of many autoimmune and inflammatory conditions, including multiple sclerosis, arthritis and colitis. Therefore, a better understanding of the molecules and pathways in TH17 is essential for our efforts to prevent and treat immune-mediated diseases.
|Zeng, Hu; Cohen, Sivan; Guy, Cliff et al. (2016) mTORC1 and mTORC2 Kinase Signaling and Glucose Metabolism Drive Follicular Helper T Cell Differentiation. Immunity 45:540-54|
|Wei, Jun; Long, Lingyun; Yang, Kai et al. (2016) Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat Immunol 17:277-85|
|Shrestha, Sharad; Yang, Kai; Guy, Cliff et al. (2015) Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat Immunol 16:178-87|
|Zeng, Hu; Chi, Hongbo (2015) Metabolic control of regulatory T cell development and function. Trends Immunol 36:3-12|
|Huang, Gonghua; Wang, Yanyan; Vogel, Peter et al. (2015) Control of IL-17 receptor signaling and tissue inflammation by the p38Î±-MKP-1 signaling axis in a mouse model of multiple sclerosis. Sci Signal 8:ra24|
|Yang, Kai; Chi, Hongbo (2014) Metabolic Control of Th17 Cell Generation and CNS Inflammation. J Neurol Neurophysiol Suppl 12:|
|Shrestha, Sharad; Yang, Kai; Wei, Jun et al. (2014) Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs. Proc Natl Acad Sci U S A 111:14858-63|
|Chapman, Nicole M; Chi, Hongbo (2014) mTOR signaling, Tregs and immune modulation. Immunotherapy 6:1295-311|
|Wei, Jun; Yang, Kai; Chi, Hongbo (2014) Cutting edge: Discrete functions of mTOR signaling in invariant NKT cell development and NKT17 fate decision. J Immunol 193:4297-301|
|Mahmud, Shawn A; Manlove, Luke S; Schmitz, Heather M et al. (2014) Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat Immunol 15:473-81|
Showing the most recent 10 out of 11 publications