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.
Encephalomyelitis, Autoimmune, Experimental
Mice, Inbred C57BL
Published Version (Please cite this version)10.1172/JCI76012
Publication InfoGerriets, VA; Haeberli, L; Hale, LP; Huck, C; Ilkayeva, Olga; Inoue, M; ... Wood, Kris Cameron (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 http://hdl.handle.net/10161/10313.
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Associate Professor of Pharmacology and Cancer Biology
Our research interests are in three interconnected areas: 1) Quantitative and computational biology of metabolism. 2) The role of diet and pharmacological therapeutics in shaping metabolic pathways in health and cancer. 3) The interaction of metabolism and epigenetics. Each of these synergistic areas utilizes the metabolomics technologies we develop along with our expertise in computational and molecular biology.
Associate Professor of Pediatrics
My laboratory is broadly interested in how large changes in nutritional status (e.g. malnutrition or obesity) influence T cell immunity. Malnutrition can lead to immunodeficiency and increased risk of infection, whereas obesity is associated with inflammation that promotes multiple diseases including autoimmunity, type 2 diabetes, and cardiovascular disease. We have identified the adipocyte-secreted hormone leptin as a critical link between nutrition and immunity. Leptin is
W. David and Sarah W. Stedman Professor of Nutrition in the School of Medicine
Over its 16 year history, our laboratory has investigated mechanisms of metabolic regulation and fuel homeostasis in mammalian systems. Major projects include: 1) Mechanisms involved in regulation of insulin secretion from pancreatic islet β-cells by glucose and other metabolic fuels; 2) Development of methods for protection of β-cells against immune-mediated damage; 3) Studies on spatial organization and regulation of systems controlling hepatic glucose balance; 4) Studies
Adjunct Associate Professor in the Department of Pharmacology and Cancer Biology
My laboratory studies the mechanisms and role of glucose metabolism in lymphocyte survival and activation. We have found that dramatic increases in glucose metabolism are necessary for lymphocytes to survive and mount immune responses. Excessive glucose metabolism, however, can lead to T cell hyperactivation and autoimmunity. A key mechanism for control of lymphocyte glucose metabolism is regulation of glucose uptake by the glucose transporter, Glut1. Interestingly, upregulation of Glut1
Associate Professor of Immunology
We need to mount a strong immune response against pathogens during infections, but excessive and uncontrolled immune reactions can lead to autoimmunity. How does our immune system keep the balance fine-tuned? This is a central question being asked in my laboratory.Immune system needs to detect pathogens quickly and effectively. This is performed by the innate immune system, which includes cells such as macrophages and dendritic cells (DCs). Pathogens are recog
Assistant Professor of Pharmacology & Cancer Biology
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