The aryl hydrocarbon receptor - Wiley Online Library

IMMUNOLOGY

REVIEW ARTICLE

The aryl hydrocarbon receptor: a molecular pathway for the environmental control of the immune response

Francisco J. Quintana Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

doi:10.1111/imm.12046 Received 03 August 2012; revised 29 October 2012; accepted 05 November 2012. Correspondence: Francisco J. Quintana, Center for Neurologic Diseases, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Email: fquintana@ rics.bwh.harvard.edu Senior author: Francisco J. Quintana

Summary Environmental factors have significant effects on the development of autoimmune diseases. The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) is controlled by endogenous and environmental small molecules. Hence, AHR provides a molecular pathway by which endogenous and environmental signals can influence the immune response and the development of autoimmune diseases. AHR also provides a target for therapeutic intervention in immune-mediated disorders. In this review, we discuss the role of AHR in the regulation of T-cell differentiation and autoimmunity. Keywords: aryl hydrocarbon receptor; autoimmunity; experimental autoimmune encephalomyelitis; multiple sclerosis; T cells.

Introduction Genetic susceptibility factors have been identified for multiple sclerosis and other autoimmune diseases, but additional factors such as environmental pollutants,1 the diet,2 the commensal flora3 and exposure to sunlight4 also play a role. Recent studies have shown that the transcription factor aryl hydrocarbon receptor (AHR) is an important regulator of the differentiation of murine and human Foxp3+ regulatory T cells,5–9 type 1 regulatory T cells5,10,11 and T helper type 17 (Th17) cells.6,12 AHR is activated by endogenous physiological ligands, some of them generated following exposure to UV light, and also by environmental ligands in pollutants, food and products of the commensal flora.13 Hence, AHR provides a pathway by which endogenous and environmental signals control multiple sclerosis -related immune processes.14 Moreover, AHR provides a target for the therapeutic manipulation of immunity. In this review, the available information on the role of AHR on the regulation of T-cell differentiation is discussed.

The aryl hydrocarbon receptor AHR signalling pathways The AHR is a ligand-activated transcription factor with a promiscuous binding pocket that can interact with a broad array of synthetic and natural ligands.15 AHR was initially identified as a receptor for dioxins like the 2,3,7,8-tetracholrodibenzo-p-dioxin (TCDD). Indeed, much of our understanding of the biology of AHR results from experiments performed using its high-affinity ligand TCDD.16 © 2012 Blackwell Publishing Ltd, Immunology, 138, 183–189

The inactive form of AHR is located in the cytoplasm as part of a protein complex that includes the 90 000 molecular weight heat-shock protein (hsp 90) and the c-SRC protein kinase. AHR ligands and hsp 90 interact with overlapping binding sites in AHR.17 On ligand binding, AHR dissociates from its complex with hsp 90 and c-SRC, translocates to the nucleus, and interacts with specific sequences (dioxin response elements) in target genes to control their transcriptional activity.18 Additional mechanisms mediating the biological effects of AHR involve its E3 ubiquitin-ligase activity19 and the modulation of the activity of other transcription factors such as nuclear factor-jB.20 To control the transcriptional activity of its target genes, AHR establishes protein–protein interactions with coactivators and other transcription factors.21 The list of transcription factors that interact with AHR includes proteins with well-characterized functions in the immune system such as signal transducers and activators of transcription (STATs), the retinoic acid receptor (RA), the oestrogen receptor (ER) and nuclear factor-jB.21 The interactions of AHR with other transcription factors result in the recognition of DNA sequences that differ from classical dioxin response elements motifs.20 Strikingly, several AHR protein interactions are only triggered by specific AHR ligands,22–24 suggesting that some transcriptional partners of AHR are recruited in a ligand-specific manner.25

Physiological AHR ligands The aryl hydrocarbon receptor was initially characterized as the receptor for dioxins, environmental pollutants generated by factories and waste-burning incinerators.13,26 183

F. J. Quintana However, the immune27 and liver defects28 observed in AHR-deficient mice suggested that natural AHR ligands play a role in normal physiology. The diet, particularly vegetables, fruits and teas, is an important source of AHR ligands.13,26 Flavonoids represent the largest group of naturally occurring dietary AHR ligands, which can have either agonist on antagonist activities on AHR activation.13,26 Usually, dietary AHR ligands have low affinity for AHR, but are converted into high-affinity ligands by poorly characterized enzymatic reactions. For example, Bradfield’s group reported that the d-amino acid oxidase enzyme generates AHR ligands from the degradation of tryptophan.29,30 In addition, several indoles, mostly derivatives of tryptophan, are AHR agonists. Examples are two tryptophan-derived AHR ligands 6-formylindolo[3,2-b]carbazole (FICZ)31 and 2-(1′ H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester32 (ITE). Notably, endogenous ligands like ITE do not induce in vivo many of the toxic effects reported for TCDD.33,34

Role of AHR signalling in the control of the T-cell response Aryl hydrocarbon receptor signalling plays an important role in the control of several components of the immune system, including T cells, B cells and the innate immune system. In this review, we will focus on the role of AHR in CD4+ T cells.

AHR signalling and Foxp3+ regulatory T cells Regulatory T (Treg) cells keep the autoreactive components of the immune system under control.35,36 A wellcharacterized population of CD4+ Treg cells is characterized by the expression of the interleukin-2 (IL-2) receptor a-chain (CD25)36 and the transcription factor Foxp3, which controls the development and function of Treg cells.37,38 The importance of Treg cells for immunoregulation is highlighted by the immune disorders that result from their removal: Treg-cell depletion from naive animals with depleting antibodies,39 as a result of thymectomy of 3-day-old newborns40,41 or by acute ablation with a toxin in Treg-cell-specific toxin receptor knock-in mice,42 results in the development of autoimmune inflammation. As deficits in the function of CD4+ CD25+ Foxp3+ Treg cells have been reported in autoimmune diseases such as multiple sclerosis,43–46 the induction of functional Foxp3+ Treg cells is viewed as a potential approach for the treatment of human autoimmune disorders.47 During the course of our studies on zebrafish adaptive immunity we identified a zebrafish Foxp3 homologue that shared molecular and functional features with its mammalian counterpart.7 Strikingly, a phylogenetic 184

footprinting analysis identified conserved dioxin response elements within the zebrafish, mouse and human Foxp3 gene, and functional studies showed that AHR controls Foxp3 expression in zebrafish,7 suggesting that AHR might also be involved in the control of FoxP3 expression in other vertebrates. Indeed, Funatake et al.48 reported that AHR activation by TCDD induces CD4+ CD25+ T cells with suppressive activity. We49 and subsequently others,50–54 found that AHR activation by its high-affinity ligand TCDD in vivo results in the expansion of the CD4+ CD25+ Foxp3+ Treg-cell compartment. These CD4+ CD25+ Foxp3+ Treg cells are functional and suppress the development of experimental autoimmune encephalomyelitis (EAE),49 experimental autoimmune uveoretinitis,54 colitis50,53 and spontaneous autoimmune diabetes.51 Several mechanisms have been involved in the expansion of Foxp3+ Treg cells by AHR activation, including the direct trans-activation of Foxp3 expression,6 the inhibition of STAT-1 signalling8 and changes in the epigenetic status of the Foxp3 locus.53 However, although TCDD is a valuable tool to investigate the immunological effects of AHR activation, TCDD is not a natural AHR ligand and its toxic properties rule out its use to treat human autoimmune disorders. Moreover, although these studies did not detect toxicity, it is not clear to what extent the expansion of Foxp3+ Treg cells resulted from preferential toxic effects of TCDD on effector T-cell populations.55 Further support for a physiological role of AHR signalling in Foxp3+ Treg cells was provided by experiments that tested the effects of non-toxic AHR ligands, such as the endogenous mucosal ligand ITE. The oral or parenteral administration of ITE expands the Foxp3+ Treg-cell compartment and treats EAE.8 Conversely, AHR-deficiency or inhibition results in decreased Foxp3+ Treg-cell differentiation.6,8,52,56 Taken together these data suggest that AHR signalling triggered by physiological ligands plays a role in the regulation of Foxp3+ Treg cells, particularly at mucosal sites where AHR can be activated by endogenous and dietary ligands, and also by bacterial products. Indeed, bacterial AHR ligands might be responsible for the AHR-dependent beneficial effects of Lactobacillus bulgaricus OLL1181 in colitis.57 In addition, the tolerogenic effects of AHR signalling might also participate in some pathological conditions, as it has been recently reported that AHR signalling is activated by tumours to evade protective immunity.58 In vivo, the promotion of Foxp3+ Treg-cell differentiation by AHR signalling involves AHR activation not only in T cells, but also in dendritic cells (DCs). The DCs stimulate and polarize T cells,59 and so balance regulatory and effector adaptive immunity. We8 and others50,56,60,61 found that AHR activation induces murine tolerogenic DCs that produce decreased pro-inflammatory cytokines and promote regulatory T-cell differentiation. Several © 2012 Blackwell Publishing Ltd, Immunology, 138, 183–189

Role of AHR in autoimmunity molecular events seem to be responsible for these effects, as AHR activation in DCs was associated with a reduction in the production of several Th1 and Th17 polarizing cytokines. In addition, this tolerogenic activity and the ability to promote the differentiation of Foxp3+ Treg cells involved the production of retinoic acid8 and tolerogenic kynurenins.56,61 We have recently used nanoparticles to activate AHR signalling and induce tolerogenic DCs that promote the differentiation of Foxp3+ Treg cells.62 Nanoparticles (NPs) have been used for in vivo tumour detection and targeting,63 for the delivery of anti-angiogenic compounds64 and also for the induction of pathogen-specific immunity in vaccination regimens.65,66 More recently, NPs have been used to deliver short-interfering RNAs to silence ccr2 expression and prevent the accumulation of inflammatory monocytes at sites of inflammation.67 We used NPs to co-administer the non-toxic AHR ligand ITE and the T-cell epitope from myelin oligodendrocyte protein located between residues 35 and 55 (MOG35–55), to promote the generation of central nervous system-specific Treg cells by DCs. The NP-treated DCs displayed a tolerogenic phenotype and promoted the differentiation of Treg cells in vitro. Moreover, NPs carrying ITE and MOG35–55 expanded the Foxp3+ Treg-cell compartment and suppressed the development of EAE, an experimental model of multiple sclerosis. The effects of NPs in vivo might also involve AHR activation in macrophages, as it has been previously shown that AHR signalling limits the inflammatory response of these cells.68,69 Hence, NPs are potential new tools for the simultaneous delivery of T-cell antigens and the activation of AHR signalling in DCs to induce antigen-specific Treg cells and treat autoimmune disorders. In mice, Foxp3 is a specific marker for Treg cells, and forced expression of Foxp337,38 or its induction with transforming growth factor-b1 (TGF-b1)70 promotes the differentiation of functional Foxp3+ Treg cells. In humans, however, FOXP3 expression is not always linked to regulatory function: activated T cells transiently express FOXP3,71,72 and forced over-expression of FOXP373 or its induction with TGF-b174 does not result in the differentiation of suppressive FOXP3+ Treg cells. Hence, additional signals besides those controlled by FOXP3 are required for the generation of human functional FOXP3+ Treg cells. We found that AHR activation in the presence of TGF-b1 induces the differentiation of functional human FOXP3+ Treg cells that suppress responder T cells via CD39. The induction of functional FOXP3+ Treg cells by the concurrent activation of TGF-b1 and AHR signalling is mediated, at least partially, by the transcription factors SMAD1 and AIOLOS. SMAD1 alone or in combination with SMAD3/4 interacts and regulates the + 2079 to + 2198 enhancer in the conserved non-coding sequence 1 of FOXP375 to activate FOXP3 expression. In addition, © 2012 Blackwell Publishing Ltd, Immunology, 138, 183–189

AIOLOS interacts with FOXP3 through its C-terminal domain and mediates the repression of IL-2 expression in FOXP3+ Treg cells induced in vitro by the concomitant activation of TGF-b1 and AHR signasling. Hence, AHR is a potential target for the generation of functional Treg cells and the treatment of autoimmune disorders. As we already mentioned, several AHR protein interactions are only triggered by specific AHR ligands,22–24 suggesting that some effects of AHR might be ligand specific. Ligand-specific effects are well characterized on other nuclear receptors, and are mainly dictated by the structure of the ligand and the cell-specific expression of receptor-interacting proteins.76–79 For example, ligandspecific effects for the ER are highly relevant for the therapy of tumours: both 17b-oestradiol and the chemotherapeutic drug tamoxifen are ER ligands; however, tamoxifen is an ER antagonist in breast tumours and an ER agonist in the endometrium whereas 17b-oestradiol is an ER agonist in both.80–84 In the case of AHR, ligandspecific effects have been reported to control its interactions with protein co-activators.22–24 Indeed, ligandspecific effects of AHR on the polarization of Foxp3+ Treg cells and other cell types have also been reported,6,53,56 but the molecular basis for those ligandspecific effects is still poorly understood.

AHR signalling and IL-10+ type 1 regulatory T cells The IL-10+ type 1 regulatory cells (Tr1 cells) were first described as suppressive CD4+ T cells induced by repeated cycles of activation in the presence of IL-10 or IL-10-conditioned DCs.85 Tr1 cells have been shown to prevent the development of colitis and other experimental autoimmune diseases.86 However, although Tr1 cells resemble natural Treg cells in some ways, they do not express Foxp3.87 Interleukin-27 promotes the differentiation of Tr1 cells,87 and IL-21 is an autocrine growth factor for Tr1 cells produced in response to IL-27.88 The transcription factor c-Maf is essential for the induction of IL-10 by Tr1 cells,89 but additional transcription factors involved in the differentiation of Tr1 cells are unknown. We found that AHR is induced by IL-27 and synergizes with c-Maf to promote the differentiation of murine and human Tr1 cells.10 AHR forms a protein complex with c-Maf, and this AHR/c-MAF complex transactivates the Il10 promoter. Moreover, we have previously shown that AHR activation up-regulates IL-21 production by T cells.6 We found that the AHR/c-Maf complex also binds and transactivates the Il21 promoter in Tr1 cells. Hence, AHR directly controls both the production of the Tr1 signature cytokine IL-10, and the production of the autocrine Tr1 growth factor IL-21. In vivo, AHR is required for the differentiation of suppressive TR1 cells capable of halting inflammation in experimental models of multiple 185

F. J. Quintana sclerosis10 and lupus.11 Moreover, we also found that AHR was important for the differentiation of human Tr1 cells.5 Hence, AHR signalling can modulate the differentiation of murine and human IL-10-producing Tr1 cells.

AHR signalling and IL-17-producing T cells Th17 cells, CD4+ T cells characterized by the production of IL-17, IL-17F, IL-21 and IL-22, play an important role in the control of specific pathogens and the development of autoimmune diseases.90–92 T-cell activation in the presence of IL-693–95 or IL-2196,97 and TGF-b1 promotes the differentiation of Th17 cells by STAT-3-dependent mechanisms,98,99 while IL-2196,97,100 and IL-23101 expand and stabilize the phenotype of Th17 cells. The signals initiated in T cells by cytokine receptors induce and activate specific transcription factors that control the transcriptional programme of Th17 cells. The differentiation of Th17 cells is driven by the transcription factors RORct102 and RORa,103 indeed mice that are deficient in RORct102 and RORa103 or mice treated with RORct inhibitors104,105 show an impaired generation of Th17 cells. In addition to RORct and RORa, other transcription factors like STAT-3 and c-Maf also participate in the differentiation of Th17 cells. The transcription factor AHR, for example, controls the expression of IL-21 and IL-22 and plays an important role in the differentiation of Th17 cells in vivo and

Endogenous ligands

DCs

in vitro.10,52,106–109 We and others reported that AHR expression is also up-regulated in Th17 cells,49,109 probably as a result of the direct transactivation of the Ahr promoter by phosphorylated STAT-3.110 Indeed, AHR ligands can boost the differentiation of Th17 cells.49,109 The activation of AHR in vivo by its ligand FICZ31 boosts the Th17 response and worsens central nervous system autoimmunity.49,109 Note, however, that similar to what has been reported for Foxp3+ Treg cells, ligand-specific effects have also been described for the differentiation of Th17 cells. Indeed, Mezrich et al.56 and Benson and Shepherd.50 have both reported inhibitory effects of specific AHR ligands on the differentiation of Th17 cells. The Th17 cells play an important role in clearing extracellular pathogens; however, an aggressive Th17 response induces severe inflammation,90 hence several mechanisms operate to prevent the dysregulated generation of pro-inflammatory Th17 cells. Interferon-c111,112 and IL-2113,114 have been identified as negative regulators of Th17 differentiation in vivo and in vitro.113 In Th17 cells, the effects of AHR might be mediated through its inhibitory interactions with STAT-152 and STAT-5,108 which might relieve the inhibitory effects of interferon-c and IL2 on Th17 cell differentiation. In addition, we recently found that under Th17 polarizing conditions AHR together with STAT-3 promote the expression of the transcription factor Aiolos, which binds to the il2

↓ IL-6 ↑ RA ↑ Kyn

FoxP3+ Treg Pollutants

Dietary ligands

Commensal flora

AHR activation

Foxp3 transactivation Foxp3 demethylation ↓ STAT-1 activation ↑ CD39 ↑ IL-2 production

Tr1 cells

↑ IL-10 ↑ IL-21 ↑ Granzyme B

Th17 cells

↑ IL-22 ↑ IL-21 ↓ STAT-5 activation ↑ Aiolos ↓ IL-2 production

Figure 1. Role of aryl hydrocarbnon receptor (AHR) signalling on CD4+ T cells. AHR signaling in FoxP3+ regulatory T (Treg) cells triggers the demethylation of Foxp3 and transactivates its promoter. AHR signalling also interferes with the activation of signal transducer and activator of transcription 1 (STAT-1), which mediates the inhibitory effects of interferon-c (IFN-c) on Foxp3+ Treg cells. Finally, AHR activation up-regulates the expression of CD39 and of Aiolos, which then inhibits interleukin-2 (IL-2) production. AHR signalling in IL-10+ type 1 regulatory (Tr1) cells triggers the expression of IL-10 and the Tr1 autocrine growth factor IL-21. In addition, AHR activation also up-regulates granzyme B expression. AHR signalling in T helper type 17 (Th17) cells promotes the expression of IL-21 and IL-22, and it also limits the activation of STAT-1 and STAT-5, which mediate the inhibitory effects of IFNc and IL-2 on Th17 cell differentiation, respectively. Finally, AHR activation inhibits the production of IL-2 through a mechanism dependent on Aiolos.

186

© 2012 Blackwell Publishing Ltd, Immunology, 138, 183–189

Role of AHR in autoimmunity promoter and induces chromatin modifications that result in il2 silencing. Aiolos-deficient naive CD4+ T cells produce larger amounts of IL-2 and show an impaired differentiation into Th17 cells, which can be reversed by blocking IL-2 function. Hence, Aiolos promotes the differentiation of Th17 cells by actively silencing IL-2 transcription under Th17-polarizing conditions. In addition to its effects on IL-21 and IL-22 production, AHR controls a module in the transcriptional programme of Th17 cells that limits the autocrine inhibitory effects of IL-2 and thereby promotes Th17 differentiation.

Concluding remarks Figure 1 summarizes our current knowledge of the role of AHR in CD4+ T cells. The identification of AHR as an important player in the development and function of effector and regulatory T cells has both basic and clinical implications: considering the abundance of AHR ligands in environmental pollutants, food and products of the commensal flora, AHR provides a molecular pathway by which the environment can affect the immune response and the development of immune-mediated disorders. Moreover, AHR constitutes a potential target for the therapeutic modulation of the immune response.

Acknowledgements Francisco J. Quintana is supported by grants AI075285, and AI093903 from the National Institutes of Health, RG4111A1 and PP1707 from the National Multiple Sclerosis Society, 17-2011-371 from the Juvenile Diabetes Research Foundation, the Harvard Digestive Diseases Center and by the Harvard Medical School Office for Diversity and Community Partnership.

Disclosure The author has no financial disclosures or competing interests.

References 1 Quintana FJ, Weiner HL. Environmental control of Th17 differentiation. Eur J Immunol 2009; 39:655–7. 2 Maslowski KM, Mackay CR. Diet, gut microbiota and immune responses. Nat Immunol 2011; 12:5–9. 3 Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science 2012; 336:1268–73. 4 Hart PH, Gorman S, Finlay-Jones JJ. Modulation of the immune system by UV radiation: more than just the effects of vitamin D? Nat Rev Immunol 2011; 11:584. 5 Gandhi R, Kumar D, Burns EJ et al. Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3+ regulatory T cells. Nat Immunol 2010; 11:846–53. 6 Quintana FJ, Basso AS, Iglesias AH et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 2008; 23:65–71. 7 Quintana FJ, Iglesias AH, Farez MF, Caccamo M, Burns EJ, Kassam N, Oukka M, Weiner HL. Adaptive autoimmunity and Foxp3-based immunoregulation in zebrafish. PLoS One 2010; 5:e9478.


8 Quintana FJ, Murugaiyan G, Farez MF, Mitsdoerffer M, Tukpah AM, Burns EJ, Weiner HL. An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 2010; 107:20768–73. 9 Yeste A, Nadeau M, Burns EJ, Weiner HL, Quintana FJ. Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 2012; 109:11270–5. 10 Apetoh L, Quintana FJ, Pot C et al. The aryl hydrocarbon receptor interacts with cMaf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat Immunol 2010; 11:854–61. 11 Wu HY, Quintana FJ, da Cunha AP, Dake BT, Koeglsperger T, Starossom SC, Weiner HL. In vivo induction of Tr1 cells via mucosal dendritic cells and AHR signaling. PLoS One 2011; 6:e23618. 12 Quintana FJ, Jin H, Burns EJ et al. Aiolos promotes Th17 cell differentiation by directly silencing il2 expression. Nat Immunol 2012; 13:770–7. 13 Denison MS, Nagy SR. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu Rev Pharmacol Toxicol 2003; 43:309–34. 14 Stevens EA, Mezrich JD, Bradfield CA. The aryl hydrocarbon receptor: a perspective on potential roles in the immune system. Immunology 2009; 127:299–311. 15 Nguyen LP, Bradfield CA. The search for endogenous activators of the aryl hydrocarbon receptor. Chem Res Toxicol 2008; 21:102–16. 16 Marshall NB, Kerkvliet NI. Dioxin and immune regulation: emerging role of aryl hydrocarbon receptor in the generation of regulatory T cells. Ann N Y Acad Sci 2010; 1183:25–37. 17 Soshilov A, Denison MS. Ligand displaces heat shock protein 90 from overlapping binding sites within the aryl hydrocarbon receptor ligand-binding domain. J Biol Chem 2011; 286:35275–82. 18 Beischlag TV, Luis Morales J, Hollingshead BD, Perdew GH. The aryl hydrocarbon receptor complex and the control of gene expression. Crit Rev Eukaryot Gene Expr 2008; 18:207–50. 19 Ohtake F, Baba A, Takada I et al. Dioxin receptor is a ligand-dependent E3 ubiquitin ligase. Nature 2007; 446:562. 20 Patel RD, Murray IA, Flaveny CA, Kusnadi A, Perdew GH. Ah receptor represses acute-phase response gene expression without binding to its cognate response element. Lab Invest 2009; 89:695. 21 Hankinson O. Role of coactivators in transcriptional activation by the aryl hydrocarbon receptor. Arch Biochem Biophys 2005; 433:379–86. 22 Boronat S, Casado S, Navas JM, Pina B. Modulation of aryl hydrocarbon receptor transactivation by carbaryl, a nonconventional ligand. FEBS J 2007; 274:3327–39. 23 Murray IA, Morales JL, Flaveny CA, Dinatale BC, Chiaro C, Gowdahalli K, Amin S, Perdew GH. Evidence for ligand-mediated selective modulation of aryl hydrocarbon receptor activity. Mol Pharmacol 2010; 77:247–54. 24 Zhang S, Rowlands C, Safe S. Ligand-dependent interactions of the Ah receptor with coactivators in a mammalian two-hybrid assay. Toxicol Appl Pharmacol 2008; 227:196– 206. 25 Murray IA, Morales JL, Flaveny CA, Dinatale BC, Chiaro C, Gowdahalli K, Amin S, Perdew GH. Evidence for ligand-mediated selective modulation of aryl hydrocarbon receptor activity. Mol Pharmacol 2010; 77:247–54. 26 Denison MS, Pandini A, Nagy SR, Baldwin EP, Bonati L. Ligand binding and activation of the Ah receptor. Chem Biol Interact 2002; 141:3–24. 27 Temchura VV, Frericks M, Nacken W, Esser C. Role of the aryl hydrocarbon receptor in thymocyte emigration in vivo. Eur J Immunol 2005; 35:2738–47. 28 Fernandez-Salguero P, Pineau T, Hilbert DM et al. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science 1995; 268:722–6. 29 Chowdhury G, Dostalek M, Hsu EL, Nguyen LP, Stec DF, Bradfield CA, Guengerich FP. Structural identification of DIINDOLE agonists of the aryl hydrocarbon receptor derived from degradation of Indole-3-pyruvic acid. Chem Res Toxicol 2009; 22:1905–12. 30 Nguyen LP, Hsu EL, Chowdhury G, Dostalek M, Guengerich FP, Bradfield CA. D-Amino acid oxidase generates agonists of the aryl hydrocarbon receptor from D-tryptophan. Chem Res Toxicol 2009; 22:1897–904. 31 Wei YD, Helleberg H, Rannug U, Rannug A. Rapid and transient induction of CYP1A1 gene expression in human cells by the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole. Chem Biol Interact 1998; 110:39–55. 32 Song J, Clagett-Dame M, Peterson RE, Hahn ME, Westler WM, Sicinski RR, DeLuca HF. A ligand for the aryl hydrocarbon receptor isolated from lung. Proc Natl Acad Sci U S A 2002; 99:14694–9. 33 Heath-Pagliuso S, Rogers WJ, Tullis K, Seidel SD, Cenijn PH, Brouwer A, Denison MS. Activation of the Ah receptor by tryptophan and tryptophan metabolites. Biochemistry 1998; 37:11508–15. 34 Henry EC, Bemis JC, Henry O, Kende AS, Gasiewicz TA. A potential endogenous ligand for the aryl hydrocarbon receptor has potent agonist activity in vitro and in vivo. Arch Biochem Biophys 2006; 450:67–77.

187

F. J. Quintana 35 Josefowicz SZ, Lu L-F, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 2012; 30:531–64. 36 Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004; 22:531–62. 37 Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat Immunol 2003; 4:330–6.

nogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci U S A 2010; 107:19961–6. 62 Yeste A, Nadeau M, Burns EJ, Weiner HL, Quintana FJ. Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 2012; 109:11270–5. 63 Qian X, Peng XH, Ansari DO et al. In vivo tumor targeting and spectroscopic detec-

38 Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299:1057–61. 39 Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor a-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155:1151–64.

tion with surface-enhanced Raman nanoparticle tags. Nat Biotechnol 2008; 26:83–90. 64 Benny O, Fainaru O, Adini A et al. An orally delivered small-molecule formulation with antiangiogenic and anticancer activity. Nat Biotechnol 2008; 26:799–807. 65 Jewell CM, Bustamante L opez SC, Irvine DJ. In situ engineering of the lymph node microenvironment via intranodal injection of adjuvant-releasing polymer particles. Proc Natl Acad Sci U S A 2011; 108:15745–50.

40 Sakaguchi S, Takahashi T, Nishizuka Y. Study on cellular events in postthymectomy autoimmune oophoritis in mice I. Requirement of Lyt-1 effector cells for oocytes damage after adoptive transfer. J Exp Med 1982; 156:1565–76. 41 Taguchi O, Nishizuka Y. Autoimmune oophoritis in thymectomized mice: T cell requirement in adoptive cell transfer. Clin Exp Immunol 1980; 42:324–31. 42 Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 2007; 8:191–7.

66 Kasturi SP, Skountzou I, Albrecht RA et al. Programming the magnitude and persistence of antibody responses with innate immunity. Nature 2011; 470:543–7. 67 Leuschner F, Dutta P, Gorbatov R et al. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat Biotechnol 2011; 29:1005–10. 68 Sekine H, Mimura J, Oshima M et al. Hypersensitivity of aryl hydrocarbon receptordeficient mice to lipopolysaccharide-induced septic shock. Mol Cell Biol 2009; 29: 6391–400.

43 Feger U, Luther C, Poeschel S, Melms A, Tolosa E, Wiendl H. Increased frequency of CD4+ CD25+ regulatory T cells in the cerebrospinal fluid but not in the blood of multiple sclerosis patients. Clin Exp Immunol 2007; 147:412–8. 44 Haas J, Hug A, Viehover A et al. Reduced suppressive effect of CD4+ CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. Eur J Immunol 2005; 35:3343–52.

69 Kimura A, Naka T, Nakahama T, Chinen I, Masuda K, Nohara K, Fujii-Kuriyama Y, Kishimoto T. Aryl hydrocarbon receptor in combination with Stat1 regulates LPSinduced inflammatory responses. J Exp Med 2009; 206:2027–35. 70 Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM. Conversion of peripheral CD4+CD25– naive T cells to CD4+CD25+ regulatory T cells by TGF-b induction of transcription factor Foxp3. J Exp Med 2003; 198:1875–86.

45 Kumar M, Putzki N, Limmroth V et al. CD4+CD25+FoxP3+ T lymphocytes fail to suppress myelin basic protein-induced proliferation in patients with multiple sclerosis. J Neuroimmunol 2006; 180:178–84. 46 Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 2004; 199:971–9.

71 Allan SE, Crome SQ, Crellin NK, Passerini L, Steiner TS, Bacchetta R, Roncarolo MG, Levings MK. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol 2007; 19:345–54. 72 Wang J, Ioan-Facsinay A, Van der Voort EI, Huizinga TW, Toes RE. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol 2007; 37:129–38.

47 Sakaguchi S, Powrie F, Ransohoff RM. Re-establishing immunological self-tolerance in autoimmune disease. Nat Med 2012; 18:54–8. 48 Funatake CJ, Marshall NB, Steppan LB, Mourich DV, Kerkvliet NI. Cutting edge: activation of the aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin generates a population of CD4+ CD25+ cells with characteristics of regulatory T cells. J Immunol 2005; 175:4184–8. 49 Quintana FJ, Basso AS, Iglesias AH et al. Control of Treg and TH17 cell differentiation

73 Allan SE, Passerini L, Bacchetta R et al. The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J Clin Invest 2005; 115:3276–84. 74 Tran DQ, Ramsey H, Shevach EM. Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-b dependent but does not confer a regulatory phenotype. Blood 2007; 110:2983–90. 75 Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature

by the aryl hydrocarbon receptor. Nature 2008; 23:23. 50 Benson JM, Shepherd DM. Aryl hydrocarbon receptor activation by TCDD reduces inflammation associated with Crohn’s disease. Toxicol Sci 2011; 120:68–78. 51 Kerkvliet NI, Steppan LB, Vorachek W, Oda S, Farrer D, Wong CP, Pham D, Mourich DV. Activation of aryl hydrocarbon receptor by TCDD prevents diabetes in NOD mice and increases Foxp3+ T cells in pancreatic lymph nodes. Immunotherapy 2009; 1:539–47.

2010; 463:808–12. 76 Gronemeyer H, Gustafsson JA, Laudet V. Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 2004; 3:950–64. 77 Hestermann EV, Brown M. Agonist and chemopreventative ligands induce differential transcriptional cofactor recruitment by aryl hydrocarbon receptor. Mol Cell Biol 2003; 23:7920–5.

52 Kimura A, Naka T, Nohara K, Fujii-Kuriyama Y, Kishimoto T. Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells. Proc Natl Acad Sci U S A 2008; 105:9721–6. 53 Singh NP, Singh UP, Singh B, Price RL, Nagarkatti M, Nagarkatti PS. Activation of aryl hydrocarbon receptor (AhR) leads to reciprocal epigenetic regulation of FoxP3 and IL-17 expression and amelioration of experimental colitis. PLoS One 2011; 6: e23522.

78 Smith CL, O’Malley BW. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev 2004; 25:45–71. 79 Wang S, Ge K, Roeder RG, Hankinson O. Role of mediator in transcriptional activation by the aryl hydrocarbon receptor. J Biol Chem 2004; 279:13593–600. 80 Conzen SD. Current status of selective estrogen receptor modulators (SERMs). Cancer J 2003; 9:4–14. 81 Jordan VC. Antiestrogens and selective estrogen receptor modulators as multifunc-

54 Zhang L, Ma J, Takeuchi M et al. Suppression of experimental autoimmune uveoretinitis by inducing differentiation of regulatory T cells via activation of aryl hydrocarbon receptor. Invest Ophthalmol Vis Sci 2010; 51:2109–17. 55 Veiga-Parga T, Suryawanshi A, Rouse BT. Controlling viral immuno-inflammatory lesions by modulating aryl hydrocarbon receptor signaling. PLoS Pathog 2011; 7: e1002427.

tional medicines. 1. Receptor interactions. J Med Chem 2003; 46:883–908. 82 Klinge CM. Estrogen receptor interaction with co-activators and co-repressors. Steroids 2000; 65:227–51. 83 Krishnan V, Heath H, Bryant HU. Mechanism of action of estrogens and selective estrogen receptor modulators. Vitam Horm 2000; 60:123–47. 84 Wallace OB, Richardson TI, Dodge JA. Estrogen receptor modulators: relationships of

56 Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol 2010; 185:3190–8. 57 Takamura T, Harama D, Fukumoto S et al. Lactobacillus bulgaricus OLL1181 activates the aryl hydrocarbon receptor pathway and inhibits colitis. Immunol Cell Biol 2011; 89:817. 58 Opitz CA, Litzenburger UM, Sahm F et al. An endogenous tumour-promoting ligand

ligand structure, receptor affinity and functional activity. Curr Top Med Chem 2003; 3:1663–82. 85 Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997; 389:737–42. 86 Battaglia M, Gregori S, Bacchetta R, Roncarolo MG. Tr1 cells: from discovery to their clinical application. Semin Immunol 2006; 18:120–7.

of the human aryl hydrocarbon receptor. Nature 2011; 478:197–203. 59 Smits HH, de Jong EC, Wierenga EA, Kapsenberg ML. Different faces of regulatory DCs in homeostasis and immunity. Trends Immunol 2005; 26:123–9. 60 Hauben E, Gregori S, Draghici E, Migliavacca B, Olivieri S, Woisetschlager M, Roncarolo MG. Activation of the aryl hydrocarbon receptor promotes allograft-specific tolerance through direct and dendritic cell-mediated effects on regulatory T cells.

87 Awasthi A, Carrier Y, Peron JP et al. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol 2007; 8:1380–9. 88 Awasthi A, Riol-Blanco L, Jager A et al. Cutting edge: IL-23 receptor gfp reporter mice reveal distinct populations of IL-17-producing cells. J Immunol 2009; 182: 5904–8. 89 Pot C, Jin H, Awasthi A et al. Cutting edge: IL-27 induces the transcription factor c-

Blood 2008; 112:1214–22. 61 Nguyen NT, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara K, Fujii-Kuriyama Y, Kishimoto T. Aryl hydrocarbon receptor negatively regulates dendritic cell immu-

Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J Immunol 2009; 183:797–801.

188


Role of AHR in autoimmunity 90 Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol 2009; 27:485–517. 91 Morrison PJ, Ballantyne SJ, Kullberg MC. Interleukin-23 and T helper 17-type responses in intestinal inflammation: from cytokines to T-cell plasticity. Immunology 2011; 133:397–408. 92 Peck A, Mellins ED. Plasticity of T-cell phenotype and function: the T helper type 17

102 Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORct directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 2006; 126:1121–33. 103 Yang XO, Pappu BP, Nurieva R et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR a and ROR c. Immunity 2008; 28:29–39. 104 Huh JR, Leung MW, Huang P et al. Digoxin and its derivatives suppress TH17 cell

example. Immunology 2010; 129:147–53. 93 Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441:235–8. 94 Mangan PR, Harrington LE, O’Quinn DB et al. Transforming growth factor-b induces development of the TH17 lineage. Nature 2006; 441:231–4.

differentiation by antagonizing RORct activity. Nature 2011; 472:486–90. 105 Solt LA, Kumar N, Nuhant P et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 2011; 472:491–4. 106 Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, Grigorieva EF, Wilhelm C, Veldhoen M. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 2011; 147:629–40.

95 Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFb in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006; 24:179–89. 96 Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 2007; 448:484–7. 97 Nurieva R, Yang XO, Martinez G et al. Essential autocrine regulation by IL-21 in the

107 Quintana FJ, Basso AS, Iglesias AH et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 2008; 453:65–71. 108 Veldhoen M, Hirota K, Christensen J, O’Garra A, Stockinger B. Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J Exp Med 2009; 206:43–9. 109 Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, Stockinger B. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environ-

generation of inflammatory T cells. Nature 2007; 448:480–3. 98 Harris TJ, Grosso JF, Yen HR et al. Cutting edge: an in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. J Immunol 2007; 179:4313–7. 99 Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol

mental toxins. Nature 2008; 453:106–9. 110 Durant L, Watford WT, Ramos HL et al. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity 2010; 32:605–15. 111 Kimura A, Naka T, Kishimoto T. IL-6-dependent and -independent pathways in the development of interleukin 17-producing T helper cells. Proc Natl Acad Sci U S A 2007; 104:12099–104.

Chem 2007; 282:9358–63. 100 Bauquet AT, Jin H, Paterson AM, Mitsdoerffer M, Ho IC, Sharpe AH, Kuchroo VK. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat Immunol 2009; 10:167–75. 101 McGeachy MJ, Chen Y, Tato CM et al. The interleukin 23 receptor is essential for the

112 Villarino AV, Gallo E, Abbas AK. STAT1-activating cytokines limit Th17 responses through both T-bet-dependent and -independent mechanisms. J Immunol (Baltimore, Md: 1950) 2010; 185:6461–71. 113 Laurence A, Tato CM, Davidson TS et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 2007; 26:371–81. 114 Yang X-P, Ghoreschi K, Steward-Tharp SM et al. Opposing regulation of the locus

terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol 2009; 10:314–24.

encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat Immunol 2011; 12:247.


189