T‐bet over‐expression regulates aryl hydrocarbon receptor‐mediated T helper type 17 differentiation through an interferon (IFN)γ‐independent pathway

Summary Various transcription factors are also known to enhance or suppress T helper type 17 (Th17) differentiation. We have shown previously that the development of collagen‐induced arthritis was suppressed in T‐bet transgenic (T‐bet Tg) mice, and T‐bet seemed to suppress Th17 differentiation through an interferon (IFN)‐γ‐independent pathway, although the precise mechanism remains to be clarified. The present study was designed to investigate further the mechanisms involved in the regulation of Th17 differentiation by T‐bet over‐expression, and we found the new relationship between T‐bet and aryl hydrocarbon receptor (AHR). Both T‐bet Tg mice and IFN‐γ –/– ‐over‐expressing T‐bet (T‐bet Tg/IFN‐γ –/– ) mice showed inhibition of retinoic acid‐related orphan receptor (ROR)γt expression and IL‐17 production by CD4 + T cells cultured under conditions that promote Th‐17 differentiation, and decreased IL‐6 receptor (IL‐6R) expression and signal transducer and activator of transcription‐3 (STAT‐3) phosphorylation in CD4 + T cells. The mRNA expression of ahr and rorc were suppressed in CD4 + T cells cultured under Th‐17 conditions from T‐bet Tg mice and T‐bet Tg/IFN‐γ –/– mice. CD4 + T cells of wild‐type (WT) and IFN‐γ –/– mice transduced with T‐bet‐expressing retrovirus also showed inhibition of IL‐17 production, whereas T‐bet transduction had no effect on IL‐6R expression and STAT‐3 phosphorylation. Interestingly, the mRNA expression of ahr and rorc were suppressed in CD4 + T cells with T‐bet transduction cultured under Th17 conditions. The enhancement of interleukin (IL)−17 production from CD4 + T cells by the addition of AHR ligand with Th17 conditions was cancelled by T‐bet over‐expression. Our findings suggest that T‐bet over‐expression‐induced suppression of Th17 differentiation is mediated through IFN‐γ‐independent AHR suppression.