Mitochondrial Transcription Factor A Regulates Foxp3+ T Cell Mediated Maintenance of CD4+ T Cell Landscapes and Immunological Aging

Abstract

AbstractA decline in mitochondrial activity has been linked to T cell dysfunction and the progression of a variety of diseases. It is unclear whether the mitochondrial function in regulatory T cells (Tregs) determines effector T cell fate decisions and regulates steady-state inflammation. We show that loss of Mitochondrial Transcription Factor A in Foxp3+ Tregs (TFAM cKO) affects the cellular and transcriptional dynamics of CD4+ T cells, resulting in disproportional cellular heterogeneity and prevalence of pathogenic CD4+ T cell subsets. Failure to modulate CD4+ T cell responses results in systemic inflammation, immunological aging, and shortened lifespans in TFAM cKO mice. Furthermore, we found that TFAM heterozygous (Het) mice with 50% allelic restoration had a progressive decrease in physiological, cognitive, and neuromuscular activity starting at 8 months, implying that the TFAM Het mouse model has the potential to be used for in-depth research on age-related inflammatory diseases. Overall, TFAM depletion in Tregs explains the steady-state reduction in Treg function with age. TFAM restoration in Tregs could be a target for preserving the homeostatic CD4+ T cell pool and avoiding cognitive impairments caused by inflammation induced aging (inflammaging).