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Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation.

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Date
2015-01
Authors
Gerriets, Valerie A
Kishton, Rigel J
Nichols, Amanda G
Macintyre, Andrew N
Inoue, Makoto
Ilkayeva, Olga
Winter, Peter S
Liu, Xiaojing
Priyadharshini, Bhavana
Slawinska, Marta E
Haeberli, Lea
Huck, Catherine
Turka, Laurence A
Wood, Kris C
Hale, Laura P
Smith, Paul A
Schneider, Martin A
MacIver, Nancie J
Locasale, Jason W
Newgard, Christopher B
Shinohara, Mari L
Rathmell, Jeffrey C
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Abstract
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.
Type
Journal article
Subject
Animals
CD4-Positive T-Lymphocytes
Cell Differentiation
Cell Proliferation
Cell Survival
Cells, Cultured
Encephalomyelitis, Autoimmune, Experimental
Energy Metabolism
Glycolysis
Mice, Inbred C57BL
Protein-Serine-Threonine Kinases
T-Lymphocytes, Regulatory
Th17 Cells
Transcriptome
Permalink
https://hdl.handle.net/10161/10313
Published Version (Please cite this version)
10.1172/JCI76012
Publication Info
Gerriets, Valerie A; Kishton, Rigel J; Nichols, Amanda G; Macintyre, Andrew N; Inoue, Makoto; Ilkayeva, Olga; ... Rathmell, Jeffrey C (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.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Hale

Laura Pope Hale

Professor of Pathology
The Hale laboratory employs techniques of cellular and molecular biology to study mechanisms responsible for the generation of both normal immune responses and immune-mediated diseases. Research in the laboratory is mainly focused on inflammatory bowel disease (IBD), an immune-mediated disorder that is hypothesized to result from the abnormal immune response of a genetically susceptible host to the antigens derived from enteric bacteria. Development of optimal treatments for disease require

Olga Ilkayeva

Assistant Professor in Medicine
Locasale

Jason Locasale

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.
MacIver

Nancie Jo MacIver

Adjunct Associate Professor in the Department 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
MacIntyre

Andrew Neil MacIntyre

Assistant Professor in Medicine
Newgard

Christopher Bang Newgard

W. David and Sarah W. Stedman Distinguished 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
Rathmell

Jeffrey Charles Rathmell

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
Shinohara

Mari L. Shinohara

Associate Professor of Immunology
Shinohara Lab WebsiteImmune responses against pathogens are essential for host protection, 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. The immune system needs to detect pathogens quickly and effectively. This is performed by the innate immune system, which includes cells such as mac
Wood

Kris Cameron Wood

Associate Professor of Pharmacology and Cancer Biology
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