Cytokine Regulation in Human CD4 T Cells by the Aryl Hydrocarbon Receptor and Gq-Coupled Receptors

Jeremy P Mcaleer,James Denvir,Bryanna Roar,Donald A Primerano,Jun Fan

doi:10.1038/s41598-018-29262-4

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. Several of the AhR-dependent genes have known roles in cellular assembly, organization, development, growth and proliferation. 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. Under neutral Th0 conditions, ogerin and the Gq/11 receptor inhibitor YM254890 blunted IL-22 induction by FICZ. These data reveal the AhR-dependent transcriptome in human CD4 T cells and suggest the mechanism through which the AhR regulates T cell function may be partially dependent on Gq-coupled receptors including GPR68.

Highlights

The aryl hydrocarbon receptor (AhR) is activated by many endogenous ligands and natural products that have disparate effects on inflammation and T cells[11]
To determine the kinetics of gene expression associated with human Th17 cell differentiation in the presence of AhR modulators, naïve CD4 T cells from peripheral blood of healthy volunteers were cultured with Th17-inducing cytokines (IL-6, TGF-β, IL-1β, IL-23) for 1–6 days
This effect was dependent on Th17-inducing cytokines, as RORC was downregulated from days 1–4 in Th0 cultures with CH223191 (Supplementary Fig. S1)

Summary

Introduction

The aryl hydrocarbon receptor (AhR) is activated by many endogenous ligands and natural products that have disparate effects on inflammation and T cells[11]. To study the mechanism of AhR regulation of cytokine production, we performed RNA-seq on T cells derived from peripheral blood of six healthy human volunteers treated with an agonist or antagonist. Activation of GPR68 with a positive allosteric modulator suppressed IL-22 and IL-10 production from human CD4 T cells cultured with Th17-inducing cytokines. Under neutral Th0 conditions, ogerin and the Gq/11 inhibitor YM254890 partially suppressed IL-22 induction by FICZ These data suggest that pro- versus anti-inflammatory effects of AhR may be partially regulated by Gq/11 receptors including GPR68. We speculate this pathway may regulate inflammation in peripheral tissues with extracellular acidification

Methods

Results

Conclusion