Cytokine regulation in human CD4 T cells by the Aryl Hydrocarbon Receptor and GPR68

Abstract

Abstract Th17 cells contribute to host defense on mucosal surfaces but also provoke autoimmune diseases when directed against self-antigens. Identifying therapeutic targets that regulate Th17 cell differentiation and/or cytokine production has considerable value. Here, we study the aryl hydrocarbon receptor (AhR)-dependent transcriptome in human CD4 T cells treated with Th17-inducing cytokines. We show that the AhR reciprocally regulates IL-17 and IL-22 production in human CD4 T cells. Global gene expression analysis revealed that AhR ligation decreased IL21 expression, correlating with delayed upregulation of RORC during culture with Th17-inducing cytokines. We further show that expression of GPR15, GPR55 and GPR68 positively correlates with IL-22 production in the presence of the AhR agonist FICZ. Activation of GPR68 with the lorazepam-derivative ogerin resulted in suppression of IL-22 and IL-10 secretion by T cells, with no effect on IL-17. These data reveal a novel feedback inhibitory pathway on IL-22 and IL-10 production in the presence of AhR agonists.