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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI105887-04
Application #
9204369
Study Section
Special Emphasis Panel (ZRG1-IMM-J (02)M)
Program Officer
Esch, Thomas R
Project Start
2014-02-15
Project End
2019-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
4
Fiscal Year
2017
Total Cost
$437,500
Indirect Cost
$187,500
Name
St. Jude Children's Research Hospital
Department
Type
Independent Hospitals
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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