Reciprocal regulation of IL-17 and IL-22 secretion by CD4 T cells through the Aryl Hydrocarbon Receptor

Abstract

Abstract CD4 T cells are critical for host defense against microorganisms and direct immune responses by differentiating into specialized subsets. While Th17 cells secreting IL-17 and IL-22 contribute to vaccine immunity, they have also been implicated in autoimmune inflammation. Our goal is to understand how endogenous factors regulate Th17 cell cytokine secretion. Murine models have demonstrated that the aryl hydrocarbon receptor (AhR) can directly promote Th17 cell differentiation or provide systemic anti-inflammatory effects, suggesting that pleiotropic functions of AhR may be dependent the ligand and/or cell type studied. Tryptophan metabolites have been identified as endogenous AhR agonists that can modulate T cell immunity. Here, we examined a potential link between tryptophan metabolism and the AhR on cytokine secretion by primary human CD4 T cells cultured under Th17 conditions. L-tryptophan decreased IL-17 secretion and RORgt expression in T cells, but did not significantly affect IL-22 secretion. Similar results were observed with the tryptophan metabolite L-kynurenine. Conversely, AhR blockade decreased IL-22 with no effect on IL-17 secretion. These data suggest that IL-17 and IL-22 production are reciprocally regulated in human CD4 T cells through tryptophan availability and the AhR, and provide an avenue for therapeutic modulation of pro-inflammatory T cell responses.