Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and [Foxp3.sup.+] regulatory T cells

The aryl hydrocarbon receptor (AhR) participates in the differentiation of mouse regulatory T cells ([T.sub.reg] cells) and interleukin 17 (IL-17)-producing helper T cells ([T.sub.H]17 cells), but its role in human T cell differentiation is unknown. We investigated the role of AhR in the differentiation of human induced [T.sub.reg] cells ([iT.sub.reg] cells). We found that AhR activation promoted the differentiation of [CD4.sup.+][Foxp3.sup.-] T cells, which produce IL-10 and control responder T cells through granzyme B. However, activation of AhR in the presence of transforming growth factor-β1 induced [Foxp3.sup.+] [iT.sub.reg] cells, which suppress responder T cells through the ectonucleoside triphosphate diphosphohydrolase CD39. The induction of functional [Foxp3.sup.+] [iT.sub.reg] cells required coordinated action of the transcriptional regulators Smad1 and Aiolos. Thus, AhR is a potential target through which functional [iT.sub.reg] cells could be induced in human autoimmune disorders.