GPR65, a critical regulator of Th17 cell pathogenicity, is regulated by the CRTC2/CREB pathway

Abstract

Abstract The CREB/CRTC2 pathway has emerged as an important regulator of immune function. We have previously shown that the CREB/CRTC2 pathway modulates autoimmune disease by promoting differentiation of the pro-inflammatory T cell, Th17. Although Th17 cells protect us against specific pathogens, Th17 cells have been found to cause destruction of tissue in patients with autoimmune diseases. Using RNAseq analysis, we have identified several genes that may be regulated by CREB in Th17 cells. Of these potential CREB targets, the G protein coupled receptor 65 is uniquely expressed in Th17 cells and mice deficient in GPR65 are resistant to autoimmunity. In our study, we confirm our RNAseq analysis by quantitative QPCR and chromatin immunoprecipitation. In addition, mice deficient in CRTC2, a CREB co-activator, have decreased expression of GPR65 in Th17 cells, indicating a role for not only CREB in regulating GPR65 expression, but also for CRTC2. Using a GPR65 agonist, we see an increase in GPR65 expression and Th17 cell differentiation. Therefore, blockade of GPR65 may lead to inhibition of pathogenic Th17 cells while simultaneously leaving non-pathogenic Th17 cells untouched, protecting patients against opportunistic infection.