Predominant Requirement of Mitochondrial Transcriptional 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 at the steady state and in tumor. 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. Tfam-deficient Tregs have enhanced methylation at TSDR of Foxp3 locus. Deletion of Tfam in Tregs affects Treg homing and maintenance, resulting in tissue inflammation in colitis, but enhances tumor rejection. Thus, our work reveals a critical role for Tfam-mediated Treg respiration in regulation of inflammation and anti-tumor immunity. RNA-seq (3 replicates) and ATAC-seq (2 replicates) analysis of spleen/lymph node regulatory T cells from Tfam cKO and control female mice.