Effect of Selective Aryl Hydrocarbon Receptor Modulators on a murine model of Th17 driven Hypersensitivity Pneumonitis (HP) (163.21)

Abstract

Abstract The physiological role of Aryl Hydrocarbon Receptor (AhR) in immune response remains a key question after the discovery that AhR is an essential transcription factor for Th17 differentiation. To study the role of AhR in T cell differentiation we examined the effects of Selective AhR Modulators (SAhRMs) on antigen specific T cell response in vitro. We found that as expected, an AhR agonist enhances IL-17A production whereas a SAhRM suppresses it. However, we also found that AhR agonists suppressed production of IL-4, which was induced by the SAhRM. By contrast IFNγ was inhibited by both compounds. We also examined the effect of SAhRMs on a well established Th17 driven murine model of hypersensitivity pneumonitis mediated by a thermophile Staphylopolyspora rectivirgula (SR). Treatment of mice that have developed SR driven airway inflammation with an AhR partial antagonist or an antagonist, suppressed AhR activation in the lung. However, these AhR ligands also increased the production IL-4 by T cells in the lung, with an increase in the percentage of T cells that produce both IL-17A and IL-4. By contrast, these ligands did not suppress IFNγ or IL-17A production. Analysis of cytokine transcripts in lungs confirmed these data. This suggests that although AhR activation is required for Th17 differentiation, once cells commit to Th17 lineage, inhibiting AhR may not affect Th17 cytokine production, but may enhance the ability of these cells to produce IL-4.