GPR25 promotes the formation of lung and liver tissue-resident memory CD8 T cells

Tissue-resident memory CD8 T (T RM ) 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 T RM cell formation. Using adoptive transfer, we found that Gpr25 -deficient T cells infiltrated tissues normally after viral infection but failed to efficiently develop into T RM cells. In a tumor challenge model, Gpr25 deficiency impaired T RM cell expansion and tumor control. Single-cell transcriptomics revealed defective acquisition of stem-like T RM cell features, including expression of T cell factor 1 (TCF1). After antigen rechallenge, Gpr25 -deficient T RM cells showed impaired secondary T RM 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 T RM cell development. Our findings suggest that modulating GPR25 function may provide a therapeutic strategy to improve T RM cell responses in infection and cancer.