The aryl hydrocarbon receptor (AHR) is a transcription factor activated by ligand highly expressed on T(H)17 cells, and AHR-deficient CD4(+) T cells have impaired production of IL-17A and IL-22. Although AHR activation can exacerbate in vivo T(H)17 cell-mediated autoimmunity, accumulating data indicate that AHR is a nonpathogenic T(H)17 marker. Thus it remains unclear how AHR activation is regulated and impacts on the generation of T(H)17 subsets. Here we demonstrated that AHR pathway is activated during in vitro pathogenic T(H)17 polarization, but it is quickly downregulated. Under these conditions, additional AHR activation promoted IL-22 but not IL-17A. Interestingly, AHR high sustained expression and IL-17A promotion were only achieved when TGF beta 1 was present in the culture. In addition to the effect on AHR regulation, TGF beta 1 presented a dual role by simultaneously suppressing the T(H)17 pathogenic phenotype acquisition. This latter effect was independent of AHR stimulation, since its activation did not confer a T(H)17 anti-inflammatory profile and Ahr(-/-) cells did not upregulate any T(H)17 pathogenic marker. Through the use of EAE model, we demonstrated that AHR is still functional in encephalitogenic CD4(+) T cells and the adoptive transfer of Ahr(-/-)T(H)17 cells to recipient mice resulted in milder EAE development when compared to their WT counterparts. Altogether, our data demonstrated that although AHR is highly expressed on in vitro-generated nonpathogenic T(H)17 cells, its ligation does not shift T(H)17 cells to an anti-inflammatory phenotype. Further studies investigating the role of AHR beyond T(H)17 differentiation may provide a useful understanding of the physiopathology of autoimmune diseases.
