Assistant Professor Boston Children's Hosp., Harvard Med. Sch. Boston, Massachusetts, United States
Disclosure(s):
Xu Zhou, PhD: No financial relationships to disclose
Introduction/Rationale: PH homeostasis is essential for physiological function, and disruptions in pH are a common feature of inflammation and disease. Immune cells monitor pH changes through specialized receptors, including the proton-sensing G-protein-coupled receptor GPR65. It is widely expressed on tissue-resident immune cells and detects subtle pH variations within the physiological range (pH 7.0-7.4).
Methods: We compared WT and Gpr65 whole-body knockout mice as well as cell-type specific Gpr65 knockouts, to study the role of GPR65-mediated pH sensing in regulating tolerance to systemic inflammation.
Results: We identify GPR65 as a critical regulator of tolerance to systemic inflammation. GPR65-deficient mice exhibit markedly increased lethality following systemic bacterial infection, despite normal pathogen burden and clearance. This heightened sensitivity is recapitulated during LPS-induced sepsis. We found that late-phase IL-17A production from peritoneal γδ T cells is both necessary and sufficient to drive the enhanced lethality in Gpr65⁻/⁻ mice. Strikingly, IL-17A levels are controlled by a “dual-safe” myeloid- γδ T cell circuit: GPR65 limits myeloid-derived IL-1β and IL-23 that are required for activating γδ T-cell IL-17A production, while simultaneously constraining the intrinsic responsiveness of γδ T cells to inflammatory cues. Thus, GPR65 signaling in either compartment of the myeloid–γδ T-cell axis is sufficient to maintain tolerance to systemic inflammation. Mechanistically, GPR65-mediated pH sensing regulates both the magnitude and kinetics of IL-10 expression in myeloid cells, which is crucial for restraining IL-1β and IL-23. In γδ T cells, GPR65 dampens cytokine sensitivity through intrinsic rewiring of transcriptional programs.
Conclusion: Together, this work reveals that GPR65 enforces a “dual-safe” innate immune circuit that calibrates the balance between protective immunity and inflammatory pathology, establishing pH sensing as a fundamental environmental checkpoint in immune-mediated disease.
