Lineage commitment and maintenance are fundamental processes in a variety of biological systems. In the immune system, dysregulated T cell responses are the cause of many allergic and inflammatory disorders. TH17 cells play a key pathogenic role in Multiple sclerosis (MS) and its murine model, experimental autoimmune encephalomyelitis (EAE). A unique feature of TH17 cells is their inherent plasticity that endows mature effector TH17 cells with characteristics of other T cell subsets especially TH1 cells, but how this process is controlled and its functional significance remain elusive. Coordination of T cell metabolic programs with cell fate decisions is a fundamental process in adaptive immunity, but how metabolic pathways intersect with immune signals in T cell fate decisions and autoimmune dysregulation is poorly defined. In particular, the function of metabolic programs in effector T cell plasticity and pathogenicity remains essentially unexplored. We hypothesize that the inherent heterogeneity of TH17 cells underlies their lineage plasticity; the balance between terminal differentiation and sustained stemness depends upon mTORC1 signaling and metabolic reprogramming, and contributes to autoimmune inflammation.
Aim 1. Determine transcriptional mechanisms and developmental trajectory underlying TH17 terminal differentiation and stemness.
Aim 2. Establish the signaling and metabolic mechanisms of mTORC1 in TH17 responses.
Aim 3. Establish metabolic control and signaling circuits of TH17 plasticity. There has been little description of molecular pathways regulating TH17 lineage plasticity. We argue that insight into metabolic control of TH17 plasticity could establish a new paradigm of T cell fate control mechanisms, and manifest legitimate therapeutic opportunities for autoimmune diseases.

Public Health Relevance

Statement T cell-mediated immune dysregulation is an important cause of many human inflammatory disorders, for instance, the TH17 subset of effector T cells is highly pathogenic in autoimmune diseases including multiple sclerosis (MS), an inflammatory demyelinating disease of CNS affecting approximately 400,000 Americans. Much emphasis has been placed on molecular and transcriptional mechanisms in TH17 cell differentiation, but how the maintenance and plasticity of effector TH17 cells is regulated remains poorly defined. Hence, a better understanding of the immune signaling and metabolic processes in these cells is essential for our efforts to prevent and treat multiple sclerosis and other autoimmune diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Esch, Thomas R
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St. Jude Children's Research Hospital
United States
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Yang, Kai; Blanco, Daniel Bastardo; Chen, Xiang et al. (2018) Metabolic signaling directs the reciprocal lineage decisions of ?? and ?? T cells. Sci Immunol 3: