Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation.
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 articleSubject
AnimalsCD4-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
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https://hdl.handle.net/10161/10313Published Version (Please cite this version)
10.1172/JCI76012Publication 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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Show full item recordScholars@Duke
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
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
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.
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
Andrew Neil Macintyre
Assistant Professor in Medicine
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 i
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
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
Mari L. Shinohara
Professor of Integrative Immunobiology
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
Kris Cameron Wood
Associate Professor of Pharmacology and Cancer Biology
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://sites.duke.edu/woodlab/.
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