Requirement of Mitochondrial Transcription Factor A in Tissue-Resident Regulatory T Cell Maintenance and Function

Regulatory T cells (Tregs) are pivotal for immune suppression. Cellular metabolism is important for Treg homeostasis and function. However, the exact role of mitochondrial respiration in Tregs remains elusive. Mitochondrial transcription factor A (Tfam) is essential for mitochondrial respiration and controls mitochondrial DNA replication, transcription, and packaging. Here, we show that genetic ablation of Tfam in Tregs impairs Treg maintenance in non-lymphoid tissues in the steady state and in tumors. Tfam-deficient Tregs have reduced proliferation and Foxp3 expression upon glucose deprivation in vitro. Tfam deficiency preferentially affects gene activation in Tregs through regulation of DNA methylation, with enhanced methylation in the TSDR of the Foxp3 locus. Deletion of Tfam in Tregs affects Treg homing and stability, resulting in tissue inflammation in colitis, but enhances tumor rejection. Thus, our work reveals a critical role of Tfam-mediated mitochondrial respiration in Tregs to regulate inflammation and anti-tumor immunity. [Display omitted] •Cell-intrinsic regulation of Tregs in specific non-lymphoid tissues by Tfam•Tfam promotes Foxp3 stability through regulation of DNA methylation•Tfam ablation switches oxidative phosphorylation toward glycolysis in Tregs•Treg-specific deletion of Tfam causes tissue inflammation but enhances tumor rejection Cellular metabolism is important for regulatory T cell (Treg) homeostasis and function. Fu et al. show that mitochondrial transcription factor A (Tfam)-mediated mitochondrial respiration is critical for Treg maintenance in non-lymphoid organs and tissues in the steady state and in tumors.