Quintana FJ, Murugaiyan G, Farez MF et al.An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 107:20768-20773

Center for Neurologic Diseases, The Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2010; 107(48):20768-73. DOI: 10.1073/pnas.1009201107
Source: PubMed


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.

Download full-text


Available from: Francisco J Quintana, Sep 30, 2015
56 Reads
  • Source
    • "The overall objective of these studies was to identify high affinity AhR ligands with the ability to induce AhR-Tregs in vivo during a murine GVH response. Based on studies with TCDD, these AhR-Tregs are induced by direct activation of AhR in donor CD4+ T cells [4], [12] and differ from the Foxp3+ Tregs that are induced indirectly via AhR signaling in dendritic cells [3], [9]. Both types of Tregs likely contribute to the suppression of autoimmune and allergic diseases that has been reported following treatment with TCDD [4], [5], [15], [16], [27] as well as other AhR ligands [3], [28]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that plays multiple roles in regulation of immune and inflammatory responses. The ability of certain AhR ligands to induce regulatory T cells (Tregs) has generated interest in developing AhR ligands for therapeutic treatment of immune-mediated diseases. To this end, we designed a screen for novel Treg-inducing compounds based on our understanding of the mechanisms of Treg induction by the well-characterized immunosuppressive AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We screened a ChemBridge small molecule library and identified 10-chloro-7H-benzimidazo[2,1-a]benzo[de]Iso-quinolin-7-one (10-Cl-BBQ) as a potent AhR ligand that was rapidly metabolized and not cytotoxic to proliferating T cells. Like TCDD,10-Cl-BBQ altered donor CD4(+) T cell differentiation during the early stages of a graft versus host (GVH) response resulting in expression of high levels of CD25, CTLA-4 and ICOS, as well as several genes associated with Treg function. The Treg phenotype required AhR expression in the donor CD4(+) T cells. Foxp3 was not expressed in the AhR-induced Tregs implicating AhR as an independent transcription factor for Treg induction. Structure-activity studies showed that unsubstituted BBQ as well as 4, 11-dichloro-BBQ were capable of inducing AhR-Tregs. Other substitutions reduced activation of AhR. Daily treatment with 10-Cl-BBQ during the GVH response prevented development of GVH disease in an AhR-dependent manner with no overt toxicity. Together, our data provide strong support for development of select BBQs that activate the AhR to induce Tregs for treatment of immune-mediated diseases.
    PLoS ONE 02/2014; 9(2):e88726. DOI:10.1371/journal.pone.0088726 · 3.23 Impact Factor
  • Source
    • "For example, TCDD promotes Tregs development indirectly by inducing IDO in DCs, which enhances Foxp3 expression [88]. Along the same line, ligation of Ahr by ITE induces tolerogenic dendritic cells (DCs) that are capable of enhancing the differentiation of Tregs [89]. However, the underlying mechanisms of these modulations remain to be defined. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The immune system is regulated by distinct signaling pathways that control the development and function of the immune cells. Accumulating evidence suggest that ligation of aryl hydrocarbon receptor (Ahr), an environmentally responsive transcription factor, results in multiple cross talks that are capable of modulating these pathways and their downstream responsive genes. Most of the immune cells respond to such modulation, and many inflammatory response-related genes contain multiple xenobiotic-responsive elements (XREs) boxes upstream. Active research efforts have investigated the physiological role of Ahr in inflammation and autoimmunity using different animal models. Recently formed paradigm has shown that activation of Ahr by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 3,3'-diindolylmethane (DIM) prompts the differentiation of CD4(+)Foxp3(+) regulatory T cells (Tregs) and inhibits T helper (Th)-17 suggesting that Ahr is an innovative therapeutic strategy for autoimmune inflammation. These promising findings generate a basis for future clinical practices in humans. This review addresses the current knowledge on the role of Ahr in different immune cell compartments, with a particular focus on inflammation and autoimmunity.
    01/2014; 2014(2-3):520763. DOI:10.1155/2014/520763
  • Source
    • "In contrast to its effect on in vitro Th17 cell differentiation, TCDD strongly suppressed Th17 cell development and the induction of EAE as described previously, a phenomenon that has been associated with the induction of Treg (reviewed in [38]). Similarly the suppression of EAE by another proposed endogenous ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) was suggested to be due to the induction of Treg [17]. As all of the publications invoking induction of Treg by the AhR ligand TCDD demonstrate alterations in frequencies rather than absolute numbers, alternative interpretations for the apparent increase in Treg may apply. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The aryl hydrocarbon receptor (AhR) has been attributed with anti-inflammatory effects in the development of pathological immune responses leading to experimental autoimmune encephalomyelitis (EAE) via the induction of regulatory T cells. In agreement with previously published findings, we find that TCDD administration confers protection from EAE, however, this immuno-modulatory effect was not the consequence of de novo Treg generation, but the inhibition of Th17 cell differentiation. Systemic application of FICZ at the time of immunization also reduced EAE pathology albeit to a lesser degree than TCDD. In vitro Th17 differentiation in the presence of AhR agonists, including TCDD, promoted IL-17 and IL-22 expression, but did not induce Treg differentiation. AhR affinity influenced the amounts of IL-17 and IL-22 protein that was secreted by Th17 cells, but did not seem to affect susceptibility to EAE in vivo. Making use of conditional AhR-deficient mice, we show that the anti-inflammatory effect of TCDD depends on AhR activation in both T cells and dendritic cells, further emphasising the ability of TCDD to interfere with T effector cell differentiation in vivo. The dichotomy between the in vivo and in vitro effects of AhR reveals the complexity of the AhR pathway, which has the capacity of affecting different AhR-expressing cell types involved in mounting immune responses, thus participating in defining their outcome.
    PLoS ONE 11/2013; 8(11):e79819. DOI:10.1371/journal.pone.0079819 · 3.23 Impact Factor
Show more