TitleDistinct modes of mitochondrial metabolism uncouple T cell differentiation and function.
Publication TypeJournal Article
Year of Publication2019
AuthorsBailis, W, Shyer, JA, Zhao, J, Canaveras, JCarlos Gar, Khazal, FJAl, Qu, R, Steach, HR, Bielecki, P, Khan, O, Jackson, R, Kluger, Y, Maher, LJ, Rabinowitz, J, Craft, J, Flavell, RA
Date Published2019 07
KeywordsAcetylation, Animals, Aspartic Acid, Cell Differentiation, Cell Line, Cell Proliferation, Citric Acid, Citric Acid Cycle, Electron Transport, Female, Histones, Humans, Lymphocyte Activation, Malates, Male, Mice, Mitochondria, Succinate Dehydrogenase, Th1 Cells, Transcription, Genetic

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 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.

Alternate JournalNature
PubMed ID31217581
PubMed Central IDPMC6939459
Grant ListF31 AI133855 / AI / NIAID NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
R01 CA166025 / CA / NCI NIH HHS / United States
T32 AI7019-41 / NH / NIH HHS / United States
T32 GM065841 / GM / NIGMS NIH HHS / United States
T32 GM065841-14 / NH / NIH HHS / United States
R61 AR073048 / AR / NIAMS NIH HHS / United States
R01 GM131642 / GM / NIGMS NIH HHS / United States
R37 AR040072 / AR / NIAMS NIH HHS / United States
T32 AI007019 / AI / NIAID NIH HHS / United States
R01 HG008383 / HG / NHGRI NIH HHS / United States
R01 CA166025-04 / NH / NIH HHS / United States