Mitochondrial Integrity Regulated by Lipid Metabolism Is a Cell-Intrinsic Checkpoint for Treg Suppressive Function

Regulatory T cells (Tregs) subdue immune responses. Central to Treg activation are changes in lipid metabolism that support their survival and function. Fatty acid binding proteins (FABPs) are a family of lipid chaperones required to facilitate uptake and intracellular lipid trafficking. One family member, FABP5, is expressed in T cells, but its function remains unclear. We show that in Tregs, genetic or pharmacologic inhibition of FABP5 function causes mitochondrial changes underscored by decreased OXPHOS, impaired lipid metabolism, and loss of cristae structure. FABP5 inhibition in Tregs triggers mtDNA release and consequent cGAS-STING-dependent type I IFN signaling, which induces heightened production of the regulatory cytokine IL-10 and promotes Treg suppressive activity. We find evidence of this pathway, along with correlative mitochondrial changes in tumor infiltrating Tregs, which may underlie enhanced immunosuppression in the tumor microenvironment. Together, our data reveal that FABP5 is a gatekeeper of mitochondrial integrity that modulates Treg function. [Display omitted] •FABP5 inhibition in Tregs alters mitochondria and enhances suppression•Disrupting FABP5 in Tregs results in mtDNA release and type I IFN signaling•cGAS/-STING-dependent type I IFN signals promote Treg IL-10 production•Tumor Tregs exhibit mitochondrial alterations and a type I IFN gene signature Field et al. show that fatty acid binding protein 5 (FABP5) maintains mitochondrial integrity in regulatory T cells (Tregs). FABP5 inhibition results in mtDNA release, which triggers expression of IL-10 and promotes Treg suppressive capacity. These findings may have implications for therapeutically targeting Tregs in autoimmunity and cancer.