Acsbg1 Dependent Mitochondrial Fitness is a Metabolic Checkpoint for Tissue T <sub>reg</sub> Cell Homeostasis

Abstract

Regulatory T (Treg) cells are critical for immunological tolerance and immune homeostasis. Treg 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 Treg cell homeostasis and the function of Treg cells. Some ACSL members, a family of acyl-CoA synthase, are expressed in T cells, but their function remains unclear. Using a combination of RNA-seq and proteome analyses, we found that Acsbg1, a member of ACSL, is selectively expressed in Treg cells. We herein show that the genetic deletion and pharmacological inhibition of Acsbg1 causes not only mitochondrial dysfunction, but also dampens other metabolic pathways including glycolysis and the TCA-cycle. The extrinsic supplementation of sgAcsbg1 Treg cells with oleoyl-CoA restored the phenotype of the Treg metabolic signature. Furthermore, we also found evidence of this pathway in ST2 + effector Treg cells in the lung, which underlies the enhanced immunosuppressive capacity in the airway inflammation. Thus, Acsbg1 serves as a metabolic checkpoint governing Treg cell homeostasis and the resolution of lung inflammation.