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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IMM-J (02)M)
Program Officer
Esch, Thomas R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
St. Jude Children's Research Hospital
Independent Hospitals
United States
Zip Code
Shi, Hao; Liu, Chaohong; Tan, Haiyan et al. (2018) Hippo Kinases Mst1 and Mst2 Sense and Amplify IL-2R-STAT5 Signaling in Regulatory T Cells to Establish Stable Regulatory Activity. Immunity 49:899-914.e6
Du, Xingrong; Wen, Jing; Wang, Yanyan et al. (2018) Hippo/Mst signalling couples metabolic state and immune function of CD8?+ dendritic cells. Nature 558:141-145
Zeng, Hu; Yu, Mei; Tan, Haiyan et al. (2018) Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7-driven B lymphopoiesis. Sci Adv 4:eaar5701
Chapman, Nicole M; Zeng, Hu; Nguyen, Thanh-Long M et al. (2018) mTOR coordinates transcriptional programs and mitochondrial metabolism of activated Treg subsets to protect tissue homeostasis. Nat Commun 9:2095
Yang, Kai; Blanco, Daniel Bastardo; Chen, Xiang et al. (2018) Metabolic signaling directs the reciprocal lineage decisions of ?? and ?? T cells. Sci Immunol 3:
Yang, Kai; Blanco, Daniel Bastardo; Neale, Geoffrey et al. (2017) Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling. Nature 548:602-606
Zeng, Hu; Chi, Hongbo (2017) mTOR signaling in the differentiation and function of regulatory and effector T cells. Curr Opin Immunol 46:103-111
Shi, Lewis Zhichang; Saravia, Jordy; Zeng, Hu et al. (2017) Gfi1-Foxo1 axis controls the fidelity of effector gene expression and developmental maturation of thymocytes. Proc Natl Acad Sci U S A 114:E67-E74
Tan, Haiyan; Yang, Kai; Li, Yuxin et al. (2017) Integrative Proteomics and Phosphoproteomics Profiling Reveals Dynamic Signaling Networks and Bioenergetics Pathways Underlying T Cell Activation. Immunity 46:488-503
Zeng, Hu; Cohen, Sivan; Guy, Cliff et al. (2016) mTORC1 and mTORC2 Kinase Signaling and Glucose Metabolism Drive Follicular Helper T Cell Differentiation. Immunity 45:540-554

Showing the most recent 10 out of 21 publications