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 <i>Gpr25</i>-deficient T cells infiltrated tissues normally after viral infection but failed to efficiently develop into T_RM cells. In a tumor challenge model, <i>Gpr25</i> 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, <i>Gpr25</i>-deficient T_RM cells showed impaired secondary T_RM cell differentiation and maintenance. Moreover, <i>Gpr25</i>-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.