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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI114581-03
Application #
9225170
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Esch, Thomas R
Project Start
2015-08-15
Project End
2020-02-29
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
3
Fiscal Year
2017
Total Cost
$373,750
Indirect Cost
$123,750
Name
Nationwide Children's Hospital
Department
Type
Research Institutes
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
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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:
Gnanaprakasam, J N Rashida; Sherman, John William; Wang, Ruoning (2017) MYC and HIF in shaping immune response and immune metabolism. Cytokine Growth Factor Rev 35:63-70
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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Liu, Guangwei; Bi, Yujing; Xue, Lixiang et al. (2015) Dendritic cell SIRT1-HIF1? axis programs the differentiation of CD4+ T cells through IL-12 and TGF-?1. Proc Natl Acad Sci U S A 112:E957-65