PGC1α-mediated mitochondrial fitness promotes T_reg cell differentiation

Regulatory T (T_reg) cells play a critical role in the maintenance of immune tolerance to self-antigens and suppression of excessive immune responses. They employ a distinct metabolic profile from other CD4 T cell subsets to support their differentiation and suppressive function, which is characterized by enhanced mitochondrial metabolism. Although PGC1α is considered a master regulator of mitochondrial biogenesis and function, its role in T_reg cell differentiation remains unclear. Herein, we demonstrated that PGC1α is highly expressed in T_reg cells compared to other CD4 T cell populations. Using a pharmacological approach, we found that its transcriptional activation in iT_reg cells enhanced mitochondrial fitness, characterized by increased expression of mitochondrial genes, mitochondrial mass, and metabolic activity. Moreover, PGC1α activation enhanced both mouse and human iT_reg cell differentiation, while its inhibition reduced this process. Therefore, our findings shed light on the potential role of PGC1α as a pharmacological target when manipulating T_reg cells as a therapeutic strategy.