@article{2607,
  keywords = {Animals, Female, Male, Mice, Transcription, Genetic, Humans, Cell Proliferation, Cell Differentiation, Cell Line, Aspartic Acid, Citric Acid Cycle, Mitochondria, Acetylation, Histones, Th1 Cells, Lymphocyte Activation, Malates, Electron Transport, Citric Acid, Succinate Dehydrogenase},
  author = {Will Bailis and Justin Shyer and Jun Zhao and Juan Canaveras and Fatimah Khazal and Rihao Qu and Holly Steach and Piotr Bielecki and Omair Khan and Ruaidhri Jackson and Yuval Kluger and Louis Maher and Joshua Rabinowitz and Joe Craft and Richard Flavell},
  title = {Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function.},
  abstract = {<p>Activated CD4 T cells proliferate rapidly and remodel epigenetically before exiting the cell cycle and engaging acquired effector functions. Metabolic reprogramming from the naive state is required throughout these phases of activation. In CD4 T cells, T-cell-receptor ligation-along with co-stimulatory and cytokine signals-induces a glycolytic anabolic program that is required for biomass generation, rapid proliferation and effector function. CD4 T cell differentiation (proliferation and epigenetic remodelling) and function are orchestrated coordinately by signal transduction and transcriptional remodelling. However, it remains unclear whether these processes are regulated independently of one another by cellular biochemical composition. Here we demonstrate that distinct modes of mitochondrial metabolism support differentiation and effector functions of mouse T helper 1 (T1) cells by biochemically uncoupling these two processes. We find that the tricarboxylic acid cycle is required for the terminal effector function of T1 cells through succinate dehydrogenase (complex II), but that the activity of succinate dehydrogenase suppresses T1 cell proliferation and histone acetylation. By contrast, we show that complex I of the electron transport chain, the malate-aspartate shuttle and mitochondrial citrate export are required to maintain synthesis of\&nbsp;aspartate, which is necessary for the proliferation of T helper cells. Furthermore, we find that mitochondrial citrate export and the malate-aspartate shuttle promote histone acetylation, and specifically regulate the expression of genes involved in T cell activation. Combining genetic, pharmacological and metabolomics approaches, we demonstrate that the differentiation and terminal effector functions of T helper cells are biochemically uncoupled. These findings support a model in which the malate-aspartate shuttle, mitochondrial citrate export and complex I supply the substrates needed for proliferation and epigenetic remodelling early during T cell activation, whereas complex II consumes the substrates of these pathways, which antagonizes differentiation and enforces terminal effector function. Our data suggest that transcriptional programming acts together with a parallel biochemical network to enforce cell state.</p>
},
  year = {2019},
  journal = {Nature},
  volume = {571},
  pages = {403-407},
  month = {07/2019},
  issn = {1476-4687},
  doi = {10.1038/s41586-019-1311-3},
  language = {eng},
}