Regulation of Th17 Cell Survival by the CREB/CRTC2—GPR65 Axis: Mechanistic and Translational Insights 2249331

Abstract

Th17 cells are critical mediators of autoimmune inflammation, but the molecular pathways that sustain their survival and metabolic function remain incompletely defined. Our prior studies identified the CREB/CRTC2 transcriptional pathway as a key regulator of Th17 differentiation. Transcriptomic analyses revealed that GPR65, an acid-sensing G protein—coupled receptor, is a direct target of CREB/CRTC2. We hypothesize that GPR65 integrates cAMP—CREB/CRTC2 signaling to maintain Th17 activation and metabolic adaptation under inflammatory conditions. We used human Jurkat T cells to model T-cell activation and assess CREB/CRTC2-dependent regulation of GPR65. T-cell proliferation and survival were analyzed using CFSE and Annexin V flow cytometry. To explore functional roles, CRISPR-Cas9—based knockout of GPR65 is being developed, and in parallel, we have initiated anti-GPR65 monoclonal antibody generation for future mechanistic and therapeutic studies. Preliminary data show that activation of the CREB/CRTC2 pathway increases GPR65 expression and enhances metabolic and survival-associated gene signatures in stimulated T cells. Ongoing work will define how GPR65 loss alters these responses. These findings support a model in which CREB/CRTC2-driven GPR65 expression links extracellular acid sensing to Th17-like cell activation. This study identifies a novel CREB/CRTC2—GPR65 signaling axis that may regulate T-cell survival and function under inflammatory stress. Understanding this pathway could reveal new therapeutic strategies to modulate pathogenic Th17 responses in autoimmune disease. Joseph H. Stahlberg Foundation Immune Response Regulation: Molecular Mechanisms (IRM)