Acsbg1-dependent mitochondrial fitness is a metabolic checkpoint for tissue T_reg cell homeostasis

Regulatory T (T_reg) cells are critical for immunological tolerance and immune homeostasis. T_reg cells strongly rely on mitochondrial metabolism and show a lower level of glycolysis. However, little is known about the role of lipid metabolism in the regulation of T_reg cell homeostasis. Some members of the ACSL family of acyl-coenzyme A (CoA) synthases are expressed in T cells, but their function remains unclear. A combination of RNA-sequencing and proteome analyses shows that Acsbg1, a member of ACSL, is selectively expressed in T_reg cells. We show that the genetic deletion of Acsbg1 not only causes mitochondrial dysfunction, but it also dampens other metabolic pathways. The extrinsic supplementation of Acsbg1-deficient T_reg cells with oleoyl-CoA restores the phenotype of the T_reg metabolic signature. Furthermore, this pathway in ST2⁺ effector T_reg cells enhances immunosuppressive capacity in airway inflammation. Thus, Acsbg1 serves as a metabolic checkpoint governing T_reg cell homeostasis and the resolution of lung inflammation.