Nature https://doi.org/10.1038/s41586-019-1311-3 (2019)

T cells require mitochondrial metabolism for their exit from the naive state and to become activated. In Nature, Flavell and colleagues show that the differentiation and terminal effector functions of helper T cells are biochemically uncoupled. Through the use of genetic interference with genes encoding subunits of complex II (Sdha and Shac) or enzymes involved in the malate–aspartate shuttle (Mdh1 and Mdh2) or mitochondrial citrate export (Slc25a1 and Acly), transport systems that fuel complex I, or the pharmacological inhibition of these processes, the authors show that complex I generates the substrates needed for epigenetic remodeling, such as histone acetylation, and proliferation during differentiation of the TH1 subset of helper T cells, while complex II restricts this processes by moving carbon forward in the tricarboxylic acid cycle and thus promotes the terminal effector state in TH1 cells. These observations describe a biochemical network that acts in parallel with the transcriptional programming to enforce cell state.