Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation.
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Activation of CD4+ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4+ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, we evaluated CD4+ T cell populations in murine models and determined that inflammatory Teffs maintain high expression of glycolytic genes and rely on high glycolytic rates, while Tregs are oxidative and require mitochondrial electron transport to proliferate, differentiate, and survive. Metabolic profiling revealed that pyruvate dehydrogenase (PDH) is a key bifurcation point between T cell glycolytic and oxidative metabolism. PDH function is inhibited by PDH kinases (PDHKs). PDHK1 was expressed in Th17 cells, but not Th1 cells, and at low levels in Tregs, and inhibition or knockdown of PDHK1 selectively suppressed Th17 cells and increased Tregs. This alteration in the CD4+ T cell populations was mediated in part through ROS, as N-acetyl cysteine (NAC) treatment restored Th17 cell generation. Moreover, inhibition of PDHK1 modulated immunity and protected animals against experimental autoimmune encephalomyelitis, decreasing Th17 cells and increasing Tregs. Together, these data show that CD4+ subsets utilize and require distinct metabolic programs that can be targeted to control specific T cell populations in autoimmune and inflammatory diseases.
Published Version (Please cite this version)
Gerriets, Valerie A, Rigel J Kishton, Amanda G Nichols, Andrew N Macintyre, Makoto Inoue, Olga Ilkayeva, Peter S Winter, Xiaojing Liu, et al. (2015). Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J Clin Invest, 125(1). pp. 194–207. 10.1172/JCI76012 Retrieved from https://hdl.handle.net/10161/10313.
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Andrew Macintyre, PhD, directs the Immunology Unit within the Duke Regional Biocontainment Laboratory. The Macintyre lab team designs and performs assays to quantify immune reconstitution and immune responses. The lab specializes in multiplex cytokine arrays, flow cytometry, high-throughput ELISAs, qRT-PCR, and other molecular tests.
The assays his team develops and runs support research into biodefense and critical public health challenges. Long-running collaborative projects include the evaluation of radiation countermeasures and the development of vaccines for influenza, gonorrhea, SARS-CoV2, and other pathogens.
Olga Ilkayeva, Ph.D., is the Director of the Metabolomics Core Laboratory at Duke Molecular Physiology Institute. She received her Ph.D. training in Cell Regulation from UT Southwestern Medical Center at Dallas, TX. Her postdoctoral research in the laboratory of Dr. Chris Newgard at Duke University Medical Center focused on lipid metabolism and regulation of insulin secretion. As a research scientist at the Stedman Nutrition and Metabolism Center, Dr. Ilkayeva expanded her studies to include the development of targeted mass spectrometry analyses. Currently, she works on developing and validating quantitative mass spectrometry methods used for metabolic profiling of various biological models with emphasis on diabetes, obesity, cardiovascular disease, and the role of gut microbiome in both health and disease.
Our laboratory uses genomic and pharmacological approaches to understand how tumor dependencies are shaped by cell intrinsic factors, environmental factors, and drug treatments during the dynamic process of tumor evolution. To learn more, please visit our laboratory website: https://woodlabduke.com/.
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