Abstract
Tissue-resident memory CD8 T (TRM) cells provide critical antiviral and antitumor immunity, but the molecular pathways guiding their development are not fully defined. Here, we identify the G protein-coupled receptor GPR25, induced by TGF-β signaling, as a regulator of TRM cell formation. Using adoptive transfer, we found that Gpr25-deficient T cells infiltrated tissues normally after viral infection but failed to efficiently develop into TRM cells. In a tumor challenge model, Gpr25 deficiency impaired TRM cell expansion and tumor control. Single-cell transcriptomics revealed defective acquisition of stem-like TRM cell features, including expression of T cell factor 1 (TCF1). After antigen rechallenge, Gpr25-deficient TRM cells showed impaired secondary TRM cell differentiation and maintenance. Moreover, Gpr25-deficient T cells displayed negative enrichment of TGF-β signature genes and impaired responses to TGF-β, indicating that GPR25 enhances TGF-β signaling to promote TRM cell development. Our findings suggest that modulating GPR25 function may provide a therapeutic strategy to improve TRM cell responses in infection and cancer.