Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation
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 Smith,Martin A. Schneider,Nancie J. MacIver,Jason W. Locasale,Christopher B. Newgard,Mari L. Shinohara,Jeffrey C. Rathmell +21 more
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TLDR
In this article, the authors evaluated CD4+ T cell populations in murine models and determined that inflammatory T cells maintain high expression of glycolytic genes, while Tregs are oxidative and require mitochondrial electron transport to proliferate and differentiate.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.read more
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Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression
Chih-Hao Chang,Jing Qiu,David O’Sullivan,Michael D. Buck,Takuro Noguchi,Jonathan D. Curtis,Qiongyu Chen,Mariel Gindin,Matthew M. Gubin,Gerritje J.W. van der Windt,Elena Tonc,Robert D. Schreiber,Edward J. Pearce,Erika L. Pearce +13 more
TL;DR: It is shown that tumor-imposed metabolic restrictions can mediate T cell hyporesponsiveness during cancer, and it is found that blocking PD-L1 directly on tumors dampens glycolysis by inhibiting mTOR activity and decreasing expression of gly colysis enzymes.
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TL;DR: A brief refresher course on six of the major metabolic pathways involved in immunometabolism is provided, giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response.
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TL;DR: An updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo is provided, and the recent potential applications of basic science discoveries in the clinical setting are explored.
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TL;DR: The role of lymphocyte metabolism on immune cell development and function and the importance of “goodtenance” in immune cell function is discussed.
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Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments
Alessia Angelin,Luis Gil-de-Gómez,Satinder Dahiya,Jing Jiao,Lili Guo,Matthew H. Levine,Zhonglin Wang,William J. Quinn,Piotr K. Kopinski,Piotr K. Kopinski,Liqing Wang,Tatiana Akimova,Yujie Liu,Tricia R. Bhatti,Rongxiang Han,Benjamin L. Laskin,Joseph A. Baur,Ian A. Blair,Douglas C. Wallace,Douglas C. Wallace,Wayne W. Hancock,Ulf H. Beier +21 more
TL;DR: It is reported that the Treg transcription factor Foxp3 reprograms T cell metabolism by suppressing Myc and glycolysis, enhancing oxidative phosphorylation, and increasing nicotinamide adenine dinucleotide oxidation, which allows Tregs a metabolic advantage in low-glucose, lactate-rich environments.
References
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Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis
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