Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation
Valerie A. Gerriets, … , Mari L. Shinohara, Jeffrey C. Rathmell
Valerie A. Gerriets, … , Mari L. Shinohara, Jeffrey C. Rathmell
Published December 1, 2014
Citation Information: J Clin Invest. 2015;125(1):194-207. https://doi.org/10.1172/JCI76012.
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Research Article Immunology

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.

Authors

Valerie A. Gerriets, Rigel J. Kishton, Amanda G. Nichols, Andrew N. Macintyre, Makoto Inoue, Olga Ilkayeva, Peter S. Winter, Xiaojing Liu, Bhavana Priyadharshini, Marta E. Slawinska, Lea Haeberli, Catherine Huck, Laurence A. Turka, Kris C. Wood, Laura P. Hale, Paul A. Smith, Martin A. Schneider, Nancie J. MacIver, Jason W. Locasale, Christopher B. Newgard, Mari L. Shinohara, Jeffrey C. Rathmell

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Figure 3

Inhibition of glycolysis or mitochondrial electron transport selectively affects Teff or Treg survival, proliferation, and function.

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Inhibition of glycolysis or mitochondrial electron transport selectively...
(A) Schematic of drug treatments for B and C. (B and C) CD4+CD25– T cells were labeled with CTV and polarized in vitro for 3 days to generate Th1 or Th17 cells or Tregs. Cells were treated with 250 μM 2DG or 5 nM rotenone, and (B) proliferation or (C) transcription factor staining was assessed by flow cytometry after 72 hours. (D) Schematic of drug treatments for E and F. (E and F) CD4+CD25– T cells were polarized in vitro for 3 days, split 1:2, and cultured with IL-2 alone for an additional 2 days and then incubated with (E) 250 μM 2DG or (F) 5 nM rotenone; survival was determined by propidium iodide exclusion relative to vehicle-treated control. (G) CD4+CD25+ natural Tregs were labeled with CTV and activated in the presence of 250 μM 2DG or 5 nM rotenone, and proliferation was assessed by CTV dilution. Data are shown as mean ± SD of triplicate samples (B, E, and F), and all data are representative of at least 3 independent experiments. *P < 0.05.