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 auto-

immune diseases. The ligand-activated transcription factor aryl hydrocar-

bon 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 pro-

vides a target for therapeutic intervention in immune-mediated disorders.

In this review, we discuss the role of AHR in the regulation of T-cell dif-

ferentiation and autoimmunity.

Keywords: aryl hydrocarbon receptor; autoimmunity; experimental auto-

immune encephalomyelitis; multiple sclerosis; T cells.

Introduction

Genetic susceptibility factors have been identified for mul-

tiple sclerosis and other autoimmune diseases, but addi-

tional 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 endoge-

nous 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-tetra-

cholrodibenzo-p-dioxin (TCDD). Indeed, much of our

understanding of the biology of AHR results from experi-

ments performed using its high-affinity ligand TCDD.16

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 tran-

scriptional activity.18 Additional mechanisms mediating the

biological effects of AHR involve its E3 ubiquitin-ligase

activity19 and the modulation of the activity of other tran-

scription factors such as nuclear factor-jB.20

To control the transcriptional activity of its target genes,

AHR establishes protein–protein interactions with coacti-

vators and other transcription factors.21 The list of tran-

scription 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 ofAHR with other transcription factors result in the recogni-

tion of DNA sequences that differ from classical dioxin

response elements motifs.20 Strikingly, several AHR pro-

tein 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 gen-

erated by factories and waste-burning incinerators.13,26

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

IMMUNOLOGY REV I EW ART ICLE

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 repre-

sent 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, sev-

eral 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 ofthe 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 compo-

nents of the immune system under control.35,36 A well-

characterized population of CD4+ Treg cells is character-

ized 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 immunoregula-

tion is highlighted by the immune disorders that result

from their removal: Treg-cell depletion from naive ani-

mals with depleting antibodies,39 as a result of thymec-

tomy 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 dis-

eases 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 disor-

ders.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

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. More-

over, 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 signal-

ling 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 paren-

teral administration of ITE expands the Foxp3+ Treg-cell

compartment and treats EAE.8 Conversely, AHR-defi-

ciency 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, partic-

ularly at mucosal sites where AHR can be activated by

endogenous and dietary ligands, and also by bacterial

products. Indeed, bacterial AHR ligands might be respon-

sible for the AHR-dependent beneficial effects of Lactoba-

cillus bulgaricus OLL1181 in colitis.57 In addition, the

tolerogenic effects of AHR signalling might also partici-

pate 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 differentia-

tion 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, 183–189184

F. J. Quintana

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 com-

pounds64 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 pro-

tein 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 toler-

ogenic 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 differenti-

ation 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,

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 interac-

tions are only triggered by specific AHR ligands,22–24 sug-

gesting 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 struc-

ture of the ligand and the cell-specific expression of

receptor-interacting proteins.76–79 For example, ligand-

specific effects for the ER are highly relevant for the ther-

apy of tumours: both 17b-oestradiol and the chemo-

therapeutic drug tamoxifen are ER ligands; however,

tamoxifen is an ER antagonist in breast tumours and an

ER agonist in the endometrium whereas 17b-oestradiol isan ER agonist in both.80–84 In the case of AHR, ligand-

specific effects have been reported to control its interac-

tions with protein co-activators.22–24 Indeed, ligand-

specific 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 ligand-

specific 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 pro-

moter. 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 trans-

activates 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 dif-

ferentiation of suppressive TR1 cells capable of halting

inflammation in experimental models of multiple

© 2012 Blackwell Publishing Ltd, Immunology, 138, 183–189 185

Role of AHR in autoimmunity

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 differenti-

ation 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 pres-

ence of IL-693–95 or IL-2196,97 and TGF-b1 promotes the

differentiation of Th17 cells by STAT-3-dependent mecha-

nisms,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 pro-

gramme 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 RORctand 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

in vitro.10,52,106–109 We and others reported that AHR

expression is also up-regulated in Th17 cells,49,109 proba-

bly as a result of the direct transactivation of the Ahr pro-

moter 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 Shep-

herd.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 extra-

cellular 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 inhibi-

tory interactions with STAT-152 and STAT-5,108 which

might relieve the inhibitory effects of interferon-c and IL-

2 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↑ KynDCsEndogenous

ligands

Pollutants

Dietary ligands ↑ IL-21

↑ IL-21↑ IL-22

↑ IL-10

↑ Granzyme B

↓ STAT-1 activation

Foxp3 transactivation

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

Foxp3 demethylation

↑ CD39↑ IL-2 production

Commensalflora

FoxP3FoxP3+

TregTreg

Tr1Tr1cellscells

Th17Th17cellscells

AHRactivation

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 pro-

duction of IL-2 through a mechanism dependent on Aiolos.

© 2012 Blackwell Publishing Ltd, Immunology, 138, 183–189186

F. J. Quintana

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 dif-

ferentiation of Th17 cells by actively silencing IL-2 tran-

scription under Th17-polarizing conditions. In addition

to its effects on IL-21 and IL-22 production, AHR con-

trols 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 ther-

apeutic 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 Scle-

rosis 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.

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Role of AHR in autoimmunity