Nature https://doi.org/10.1038/s41586-018-0846-z (2019)

Regulatory T cells (Treg cells) exhibit a cellular metabolism distinct from that of CD4+ effector T cells. In Nature, Weinberg et al. show that mitochondrial complex III is required for the suppressive activity of Treg cells. Mice that conditionally lack expression of Uqcrsf1 or Uqcrq, which encode components of mitochondrial complex III, develop a scurfy-like autoimmune phenotype, and their Treg cells fail to suppress effector cells in vitro. Interestingly, expression of the transcription factor Foxp3, cytokine receptor CD25 and immunomodulatory receptors CTLA-4 and GITR is not diminished in Treg cells from mitochondrial complex III–deficient mice, nor is the Treg cellularity of those mice altered relative to that of wild-type mice. Instead, expression of the neuropilin NRP1, inhibitory receptor PD-1, AMP nucleotidase CD73 and checkpoint receptor TIGIT is lower in mitochondrial complex III–deficient Treg cells. Loss of mitochondrial complex III in Treg cells alters cellular NAD+/NADH ratios and increases cellular levels of succinate and 2-hydroxyglutarate, which are correlated with alterations in DNA-methylation patterns and altered gene expression. These findings suggest that the suppressive activity of Treg cells is more complex than previously thought.