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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 Article has an altmetric score of 20

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

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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.

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 1

Teffs, but not Tregs, upregulate glycolytic metabolism during inflammatory processes in vivo.

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Teffs, but not Tregs, upregulate glycolytic metabolism during inflammato...
(A–C) EAE was induced in 2D2 TCR transgenic mice, and RNA was extracted from spinal cords of mice with active disease or in vitro MOG-stimulated (MOG stim) 2D2 T cells as indicated (A) for real-time PCR of (B) inflammatory and (C) metabolic gene expression. (D) EAE was induced in wild-type mice and CD4+ T cells in spleens, and inguinal lymph nodes of mice with active disease were examined using flow cytometry. Data are representative of 2 experiments (A–C, n = 10; D, n = 5) and shown as mean ± SD. *P < 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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