No abstract

The immune system deteriorates as we age. Regulatory T cells contribute to immunosenescence as they critically mold antigenic CD4+ T cell subsets and maintain immunological homeostasis. Given the role of mitochondrial Transcription Factor A (TFAM) in oxidative stress, cellular senescence, and age-related pathologies, we explored the role of this factor in Regulatory T (Treg) cells. We employed a conditional deletion of FoxP3-specific TFAM to create Regulatory T (Treg) cells lacking mitochondrial TFAM. Using comprehensive single-cell RNA cell technology, we identified how mitochondrial TFAM in Treg cells controls the CD4+ T cell fate and trajectory for a heterologous pool of inflammatory CD4 cytotoxic, CD4 exhausted, and CD4 effector memory T cells, all features of aging. Additionally, our results show how TNF signalling and related cell death pathways exacerbate systemic inflammation, degradation, and acceleration of cell death in mice lacking TFAM. Furthermore, partial TFAM restoration or use of the antioxidative drug resveratrol alleviate the inflammaging cascade. These findings reveal TFAM as a critical regulator of Foxp3 Treg cell activity in sculpting the CD4 heterologous pool and point to TFAM as a possible target for pharmacological manipulation in age-related diseases.