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

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

United States

2015-07-16T18:50:24Z

2015-01

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.

http://www.ncbi.nlm.nih.gov/pubmed/25437876

76012

1558-8238

https://hdl.handle.net/10161/10313

eng

American Society for Clinical Investigation

J Clin Invest

10.1172/JCI76012

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

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

Journal article

Macintyre, Andrew N|0000-0002-5297-0207

Ilkayeva, Olga|0000-0002-9779-0883

Wood, Kris C|0000-0002-5887-2253

MacIver, Nancie J|0000-0003-3676-9391

Locasale, Jason W|0000-0002-7766-3502

Shinohara, Mari L|0000-0002-6808-9844

http://www.ncbi.nlm.nih.gov/pubmed/25437876

194

207

1

Basic Science Departments

Biochemistry

Biomedical Engineering

Clinical Science Departments

Duke

Duke Cancer Institute

Duke Human Vaccine Institute

Duke Molecular Physiology Institute

Global Health Institute

Immunology

Institutes and Centers

Institutes and Provost's Academic Units

Medicine

Medicine, Endocrinology, Metabolism, and Nutrition

Molecular Genetics and Microbiology

Pathology

Pediatrics

Pediatrics, Endocrinology

Pharmacology & Cancer Biology

Pratt School of Engineering

Sarah Stedman Nutrition & Metabolism Center

School of Medicine

University Institutes and Centers

Published

125