When naive T cells encounter foreign antigen along with proper co-stimulation and cytokines, they undergo rapid and extensive clonal expansion and differentiate into specific lineages. Two closely related lineages in CD4+ T cells are TH17 cells, which promote inflammation, and Treg, which dampen immune responses. Recent work from us and others has shown that T cell metabolic pathways are tightly and ubiquitously linked with T cell differentiation and immune functions, implicating a great potential for modulating T cell immune responses through targeting metabolic processes. Recent work from us and others indicated a preference on glycolysis during TH17 differentiation but not during iTreg differentiation, and suggests that such metabolic preferences play a role in driving cell fate towards TH17 or iTreg. These studies indicate the presence of T cell lineage- specific metabolic programs and cell intrinsic mechanisms of metabolic regulation of T cell differentiation. However, the complete profile of T cell lineage-specific metabolic programs, the regulatory mechanisms of metabolic reprogramming during T cell differentiation and the potential therapeutic application of targeting T cell metabolic programs remain elusive. Our studies to date have implicated the transcription factor Myc as one of the key nodes coordinately regulating TH17 cell metabolism and differentiation. We therefore hypothesize that the Myc-mediated metabolic reprogramming and metabolic checkpoint fuels TH17 differentiation and represents a novel therapeutic target of autoimmune diseases. Our goals follow directly from this hypothesis and we propose to apply biochemical, cellular and genetic approaches to investigate the role of Myc and metabolic reprogramming in regulating T cell differentiation. Specifically, we will: a) determine the TH17 lineage-specific metabolic reprogramming, metabolic addiction and the role of Myc in regulating TH17 metabolism and differentiation (aim 1); b) elucidate the dynamic interplay among Myc, TORC1 and HIF1? in mediating a metabolic checkpoint in TH17 differentiation (aim 2); and c) assess the metabolic program as a novel therapeutic target for TH17-mediated autoimmune diseases (aim 3). Our proposal employs genetic models and metabolic approaches and focuses on TH17 cells as a starting point to dissect how the metabolic pathway regulation impacts immune responses in physio-pathological settings. The insights generated from this study will reveal fundamental interplays between signaling pathways and metabolic pathways in the immune system. These studies of immune metabolism may identify novel therapeutic intervention strategies for inflammatory and autoimmune diseases.

Public Health Relevance

This project explores how metabolism is controlled in T cell immune responses, at the level of precise biochemical reaction, molecular interactions, amenable to pharmacologic manipulation. This is an emerging new research area that will enable us to develop novel therapeutic intervention of targeting metabolic pathways for T cell mediated inflammatory and autoimmune diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Esch, Thomas R
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Nationwide Children's Hospital
United States
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Shen, Yuqing; Sherman, John William; Chen, Xuyong et al. (2018) Phosphorylation of CDC25C by AMP-activated protein kinase mediates a metabolic checkpoint during cell-cycle G2/M-phase transition. J Biol Chem 293:5185-5199
Wang, Tingting; Liu, Lingling; Chen, Xuyong et al. (2018) MYCN drives glutaminolysis in neuroblastoma and confers sensitivity to an ROS augmenting agent. Cell Death Dis 9:220
Lu, Yun; Liu, Huanrong; Bi, Yujing et al. (2018) Glucocorticoid receptor promotes the function of myeloid-derived suppressor cells by suppressing HIF1?-dependent glycolysis. Cell Mol Immunol 15:618-629
Rashida Gnanaprakasam, Josephin N; Wu, Ruohan; Wang, Ruoning (2018) Metabolic Reprogramming in Modulating T Cell Reactive Oxygen Species Generation and Antioxidant Capacity. Front Immunol 9:1075
Lian, Gaojian; Gnanaprakasam, Jn Rashida; Wang, Tingting et al. (2018) Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation. Elife 7:
Yao, Qing; Gutierrez, David C; Hoang, Ngoc Ha et al. (2017) Efficient Codelivery of Paclitaxel and Curcumin by Novel Bottlebrush Copolymer-based Micelles. Mol Pharm 14:2378-2389
Shen, Yuqing; Vignali, Paolo; Wang, Ruoning (2017) Rapid Profiling Cell Cycle by Flow Cytometry Using Concurrent Staining of DNA and Mitotic Markers. Bio Protoc 7:
Gnanaprakasam, J N Rashida; Wang, Ruoning (2017) MYC in Regulating Immunity: Metabolism and Beyond. Genes (Basel) 8:
Liu, Lingling; Lu, Yun; Martinez, Jennifer et al. (2016) Proinflammatory signal suppresses proliferation and shifts macrophage metabolism from Myc-dependent to HIF1?-dependent. Proc Natl Acad Sci U S A 113:1564-9
Verbist, Katherine C; Guy, Cliff S; Milasta, Sandra et al. (2016) Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature 532:389-93

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