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

Tissue-resident memory (TRM) CD8+ T cells are key players that orchestrate protective anti-viral and anti-tumor immune responses. The molecules that support their development and function are not fully defined. Here, we report on the regulation and function of an orphan G-protein coupled receptor, GPR25 that is expressed at higher levels in TRM cells. TGF-b, a key cytokine involved in the development to TRM cells, induces the expression of GPR25 in CD8+ T cells, and TRM-associated cis-regulatory elements in the GPR25 locus show binding of SMAD1, key transcription factors downstream of TGF-b signaling. By using Gpr25-deficient T cells in an LCMV infection model, we show that Gpr25 acts in a cell-intrinsic manner to promote the development of both primary and secondary TRM cells in the liver. Gpr25 deficiency in T cells also impairs their capacity to develop into CD69+CD103+ TRM cells in the lungs as well as to control lung metastasis in a tumor challenge model. Single-cell transcriptomic analysis of Gpr25-deficient memory T cells and TRM cells showed potential defects in restraining the ZEB2-S1PR5 pathway that drives tissue egress and in supporting a stem-like memory program as opposed to effector differentiation. Our findings support the concept that modulating Gpr25 function may be an attractive therapeutic option to boost the magnitude and quality of TRM responses generated in the context of infection and cancer.