IL-10 producing regulatory type 1 (TR1) T cells are instrumental in the prevention of tissue inflammation, autoimmunity and graft-versus-host disease. The transcription factor c-Maf is essential for TR1 induction of IL-10, but the molecular mechanisms leading to the development of these cells remain incompletely understood. We demonstrate that the ligand–activated transcription factor aryl hydrocarbon receptor (AhR) induced by IL-27, synergizes with c-Maf to promote the development of TR1 cells. Upon T cell activation under TR1-skewing conditions, the AhR binds to c-Maf and promotes the transactivation of both Il10 and Il21 promoters, resulting in the generation of TR1 cells and amelioration of experimental autoimmune encephalomyelitis. Manipulation of AhR signaling could therefore be beneficial in the resolution of excessive inflammatory responses.

The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) participates in the differentiation of FoxP3 + T reg , Tr1 cells, and IL-17-producing T cells (Th17). Most of our understanding on the role of AHR on the FoxP3 + T reg compartment results from studies using the toxic synthetic chemical 2,3,7,8-tetrachlorodibenzo-p-dioxin. Thus, the physiological relevance of AHR signaling on FoxP3 + T reg in vivo is unclear. We studied mice that carry a GFP reporter in the endogenous foxp3 locus and a mutated AHR protein with reduced affinity for its ligands, and found that AHR signaling participates in the differentiation of FoxP3 + T reg in vivo. Moreover, we found that treatment with the endogenous AHR ligand 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) given parenterally or orally induces FoxP3 + T reg that suppress experimental autoimmune encephalomyelitis. ITE acts not only on T cells, but also directly on dendritic cells to induce tolerogenic dendritic cells that support FoxP3 + T reg differentiation in a retinoic acid-dependent manner. Thus, our work demonstrates that the endogenous AHR ligand ITE promotes the induction of active immunologic tolerance by direct effects on dendritic and T cells, and identifies nontoxic endogenous AHR ligands as potential unique compounds for the treatment of autoimmune disorders. R egulatory T cells (T reg ) that express the transcription factor FoxP3 control immune autoreactivity in healthy individuals (1). FoxP3 + T reg are generated in the thymus (natural T reg , nT reg ) and also in the periphery (induced T reg , iT reg ). The importance of FoxP3 + T reg for immunoregulation is highlighted by the immune disorders that result from their depletion or loss of function in both mice and humans (1). Conversely, the induction of FoxP3 + T reg is viewed as a promising approach for the treatment of immunemediated disorders (2).We (3) and others (4-8) have found that the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) controls the differentiation of T reg , Tr1 cells (9), and IL-17-producing T cells (Th17) in vitro and in vivo. AHR activation by its high-affinity ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in vivo results in the expansion of the CD4+ T reg compartment (3). These CD4+ T reg are functional and suppress the development of experimental autoimmune encephalomyelitis (EAE) (3), experimental autoimmune uveoretinitis (7), and spontaneous autoimmune diabetes (10).TCDD is a valuable tool to study the immunological effects of AHR activation, but TCDD is not a natural AHR ligand and its toxicity rules out its therapeutic use. Thus, it is not yet known whether there is a physiological role for AHR in FoxP3 + T reg , and whether nontoxic AHR ligands exist which can expand FoxP3 + T reg in vivo to treat autoimmunity. To address these questions, we used mice carrying a GFP reporter in foxp3 and a mutant AHR protein with reduced affinity for its ligands. In addition, we investigated the effect and mechanisms of action...

The aryl hydrocarbon receptor (AhR) participates in the differentiation of mouse regulatory T cells (T reg cells) and interleukin 17 (IL-17)-producing helper T cells (T 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 reg cells (iT reg cells). We found that AhR activation promoted the differentiation of CD4 + Foxp3 − 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 + iT reg cells, which suppress responder T cells through the ectonucleoside triphosphate diphosphohydrolase CD39. The induction of functional Foxp3 + iT reg cells required coordinated action of the transcriptional regulators Smad1 and Aiolos. Thus, AhR is a potential target through which functional iT reg cells could be induced in human autoimmune disorders.In healthy people, the immune response is controlled by several subsets of regulatory T cells (T reg cells) that are generated in the thymus (natural T reg ) and also in the periphery in response to various tolerogenic stimuli (induced T reg cells (iT reg cells) 1 . One of these subsets is a population of CD4 + T cells characterized by expression of the transcription factor Foxp3 (A002750) 1 . In mice, Foxp3 is a specific marker for T reg cells, and forced expression of Foxp3 (refs. 2,3 ) or its induction with transforming growth factor-β1 (TGF-β1) 4 promotes the differentiation of functional Foxp3 + T reg cells. In humans, however, Foxp3 expression is not always linked to regulatory function: activated T cells transiently express Foxp3 (refs. 5,6 ), and neither forced overexpression of Foxp3 (ref. 7 ) nor its induction with TGF-β1 (ref. 8 ) results in the differentiation of suppressive Foxp3 + T reg cells. Thus, additional signals beyond those controlled by Foxp3 are required for the generation of human functional Foxp3 + T reg cells.Correspondence should be addressed to F.J.Q. (fquintana@rics.bwh.harvard.edu). 3 Present address: Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Genoa, Italy.Accession codes. UCSD-Nature Signaling Gateway (http://www.signaling-gateway.org): A002750, A000229 and A003947.Note: Supplementary information is available on the Nature Immunology website. AUTHOR CONTRIBUTIONS COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/. NIH Public Access RESULTS AhR activation induces T cells that produce IL-10AhR participates in the differentiation of mouse Foxp3 + T reg cells [14][15][16][17][18] . To investigate whether AhR contributes to the differentiation of human T reg cells, we isolated naive CD4 + T cells from peripheral blood mononuclear cells obtained from healthy donors and activated them with anti-CD3, anti-CD28 and IL-2 with or without the AhR ligand TCDD ( Supplementary Fig. 1). Naive ...