Metabolism meets gene regulation

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

Regulatory T cells (T_reg 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 T_reg 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 T_reg 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 T_reg cells from mitochondrial complex III–deficient mice, nor is the T_reg 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 T_reg cells. Loss of mitochondrial complex III in T_reg 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 T_reg cells is more complex than previously thought.