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Metabolic Programming and PDHK1 Control CD4 T-Cell Subsets and Inflammation

Schneider, Martin Alexander and Smith, Paul and Slawinska, Marta Elzbieta and Haeberli, Lea and Huck, Catherine and Gerriets, Valerie and Kishton, Rigel and Nichols, Amanda and Macintyre, Andrew and Inoue, Makato and Ilkayeva, Olga and Winter, Peter and Wood, Kris and Liu, Xiaojing and Priyadharshini, Bhavana and Turka, Laurence and Hale, Laura and MacIver, Nancie and Locasale, Jason and Newgard, Christopher and Shinohara, Mari and Rathmell, Jeffrey (2015) Metabolic Programming and PDHK1 Control CD4 T-Cell Subsets and Inflammation. Jouranl of Clinical Investigation. pp. 194-207.

Abstract

CD4 T cell activation leads to rapid cell proliferation and differentiation into effector and regulatory subsets. Effector (Teff; Th1 and Th17) and regulatory (Treg) CD4 cells are metabolically distinct, yet specific metabolic differences that may modify T cell populations are uncertain. Here we show that inflammatory Teff maintained high expression of glycolytic genes in vivo and relied on high glycolytic rates while Treg were oxidative and required mitochondrial electron transport to proliferate, differentiate, and survive. Metabolic profiling revealed Pyruvate Dehydrogenase (PDH) as a key bifurcation point between T cell glycolytic or oxidative metabolism. Pyruvate Dehydrogenase Kinase (PDHK) inhibits PDH, and PDHK isoform 1 (PDHK1) was expressed in Th17, but not Th1, and at low levels in Treg. Importantly, inhibition or RNAi of PDHK1 selectively suppressed Th17 and increased Treg cells. This was mediated in part through reactive oxygen species, as generation of Th17 cells was restored by N-acetylcysteine treatment. Inhibition of PDHK1 modulated immunity in vivo and protected against experimental autoimmune encephalomyelitis with decreased Th17 and increased Treg cells. 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.

Item Type: Article
Keywords: ImmunoMetabolism, effector and regulatory T cells, inflammation autoimmune disease
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/23586

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