Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function

Nature. 2019 Jul;571(7765):403-407. doi: 10.1038/s41586-019-1311-3. Epub 2019 Jun 19.


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 activation1. 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 function2. 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 (TH1) cells by biochemically uncoupling these two processes. We find that the tricarboxylic acid cycle is required for the terminal effector function of TH1 cells through succinate dehydrogenase (complex II), but that the activity of succinate dehydrogenase suppresses TH1 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Aspartic Acid / metabolism
  • Cell Differentiation* / genetics
  • Cell Line
  • Cell Proliferation / genetics
  • Citric Acid / metabolism
  • Citric Acid Cycle
  • Electron Transport
  • Female
  • Histones / metabolism
  • Humans
  • Lymphocyte Activation / genetics
  • Malates / metabolism
  • Male
  • Mice
  • Mitochondria / metabolism*
  • Succinate Dehydrogenase / metabolism
  • Th1 Cells / cytology*
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Transcription, Genetic


  • Histones
  • Malates
  • Citric Acid
  • Aspartic Acid
  • malic acid
  • Succinate Dehydrogenase