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

  • Sci Immunol. 2025 Nov 21;10(113):eadu2089. doi: 10.1126/sciimmunol.adu2089.
Han Feng  1 ,  Sungjun Park  1 ,  Jae Woo Shin  1 ,  Francisco Emmanuel Castañeda-Castro  1 ,  Job Rocha Hernandez  1 ,  Benjamin J Schmiedel  1 ,  Changlu Liu  2 ,  Michael R Jackson  2 ,  Christian H Ottensmeier  3  4 ,  Pandurangan Vijayanand  1  3  4
Affiliations
  • 1. La Jolla Institute for Immunology, La Jolla, CA, USA.
  • 2. Conrad Preys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 3. Institute of Translational Medicine, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
  • 4. Department of Medicine, University of California, San Diego, CA, USA.
PMID: 41270189 DOI: 10.1126/sciimmunol.adu2089
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.

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