AHR Function in Lymphocytes: Emerging Concepts

doi:10.1016/j.it.2015.11.007

Trends in Immunology

Volume 37, Issue 1, January 2016, Pages 17-31

https://doi.org/10.1016/j.it.2015.11.007 Get rights and content

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Regulated expression of AHR by immunological stimuli, such as cytokines, can determine its action in the corresponding cells, thus influencing host immunity.

Tissues that are exposed to the external environmental stimuli, such as the gut and the skin, are the host milieu that is enriched in both AHR-expressing cells and in AHR ligands.

Despite a myriad of genes that can be bound by AHR in different cell types (e.g., hepatocytes) upon treatment with pollutants such as dioxin, unique gene targets of AHR might be present, especially in physiological conditions, without its activation by xenobiotic compounds.

AHR can also partner with other factors to exert its complex function in the immune system. The factors can have tissue and context-specific expression, thus presenting an additional regulatory level to AHR function.

Identification and characterization of compounds that are either derived from food, generated endogenously by the host cells, or by indigenous microbes will facilitate drug discovery by presenting strategies towards targeting the AHR pathway in different tissues and disease settings.

The aryl hydrocarbon receptor (AHR) is an important regulator of the development and function of both innate and adaptive immune cells through roles associated with AHR's ability to respond to cellular and dietary ligands. Recent findings have revealed tissue and context-specific functions for AHR in both homeostasis and in during an immune response. I review these findings here, and integrate them into the current understanding of the mechanisms that regulate AHR transcription and function. I propose a conceptual framework in which AHR function is determined by three factors: the amount of AHR in any given cell, the abundance and potency of AHR ligands within certain tissues, and the tissue microenvironment wherein AHR⁺ cells reside. This complexity emphasizes the necessity cell-type specific genetic approaches towards the study of AHR function.

Introduction

AHR is a ligand-dependent transcription factor, best known for mediating the biotransformation and carcinogenic/teratogenic effects of environmental toxins [e.g., 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD), a prototypical xenobiotic ligand for AHR]. The Ahr gene was cloned in the early 1990s 1, 2, 3, 4, and much of our understanding of AHR function initially came from studies in toxicology and pharmacology, which focused on its role in response to xenobiotics [5]. The perspective on AHR changed when it was revealed to be an important regulator of the development and function of both innate and adaptive immune cells, and that this role was mediated by the ability of AHR to respond to endogenous ligands generated from the host cell, diet, and from microbiota 6, 7, 8. AHR is currently considered to function as an environmental sensor, connecting ‘outside’ environmental signals to ‘inside’ cellular processes, with important consequences for immune cell function (Figure 1).

Recent findings have provided new insights into the role of AHR in different settings, revealing complex regulatory pathways that guide tissue and context-specific functions for AHR in both homeostasis and during an immune response 9, 10, 11. This article reviews these findings and integrates them into current understanding of the mechanisms that regulate AHR transcription and function, and the physiological and pathological roles of AHR upon activation by endogenous ligands. I propose a conceptual framework in which AHR function is determined by three factors: the amount of AHR in any given cell, the abundance and potency of AHR ligands within a particular tissue, and the tissue microenvironment wherein AHR⁺ cells reside.

Section snippets

AHR Structure and Function

AHR is a ligand-dependent nuclear receptor and belongs to the basic helix-loop-helix (bHLH)/Per–Arnt–Sim (PAS) family of proteins (Figure 2) [12]. In the absence of a ligand, AHR is retained in the cytosol and complexes with the chaperone proteins, HSP90 (heat-shock protein 90 kDa), AIP (aryl hydrocarbon receptor interacting protein, also known as XAP2 or ARA9), and p23 (also known as PTGES3). Ligand binding results in a conformational change that in turn leads to its nuclear translocation.

Transcriptional Regulation of AHR Expression

AHR is expressed in barrier tissues (e.g., the gut, the skin, and the lung) by immune cells such as lymphocytes and by tissue structural cells such as epithelial and stromal cells, and also in the liver by hepatocytes, consistent with its role as a sensor for environmental stimuli. AHR expression is regulated by environmental cues, such as cytokines [e.g., interleukin (IL)-6, IL-21, transforming growth factor (TGF)-β, and others] 22, 23, 24. The available evidence suggests that AHR expression

Regulation of AHR Activity

AHR activity is regulated in various ways. First, AHR protein levels are controlled via ubiquitin-mediated proteosomal degradation: Ligand binding induces AHR ubiquitination and subsequent degradation by the proteasome [5]. AIP, a component of the AHR chaperone complex, stabilizes AHR by inhibiting its ubiquitination 40, 41, 42. Second, an auto-regulatory feedback loop is in place, in which AHR induces the expression of negative regulators that in turn prevent excessive AHR activation. AHR

Variety of AHR Ligands

The impact of xenobiotic ligands (e.g., TCDD) on AHR function in the immune system has been reviewed elsewhere 52, 53. I focus here on endogenous and physiological AHR ligands generated by cells, the microbiota, or from dietary sources that have been shown to impact on lymphocyte development and function.

The high-affinity AHR ligand 6-formylindolo[3,2-b]carbazole (FICZ) is an ultraviolet photoproduct of L-tryptophan [54]. Recent data suggest that FICZ can also be generated by other metabolic

Complex Roles for AHR in T Cell Differentiation

In sharp contrast to earlier data showing that AHR promotes Th17 cell differentiation and IL-17/22 production by γδT cells in vitro 11, 22, recent findings revealed that AHR-deficient mice have increased Th17 and IL-17/22-producing γδT cell responses in a skin-inflammation model [61]. The role of AHR in Treg cell differentiation is also unclear. While several groups 22, 23, 62 reported the expression of AHR in Treg cells, others reported that splenic Tregs express low levels of AHR, as compared

Impact of AHR in Th17 and Th22 Cells

Differentiation of naïve CD4⁺ T cells into Th17 cells requires the transcription factor RORγt [63], and these cells are characterized by a signature cytokine profile which includes IL-22, GM-CSF (granulocyte/macrophage colony-stimulating factor), IL-17 (also known as IL-17A) and IL-17F [64]. IL-17 and IL-17F are encoded by genes located on the same chromosome and may share similar regulatory mechanisms [65]. As noted above, in vitro studies suggest that AHR promotes Th17 cell differentiation,

AHR in Treg Cell Development and Function

Although AHR is expressed by Treg cells, particularly in specific subtypes with an activated phenotype 23, 86, 87, the precise role of AHR in Treg cell development/function remains controversial [88]. A substantial body of literature suggests that xenobiotic ligand TCDD administration in vivo suppresses immune responses [52]. This immunosuppressive effect of TCDD has been linked to the expansion or induction of Treg cells and to promotion of Treg cell function in an AHR-dependent manner in mice

AHR in Tr1 Development and Function

Type 1 regulatory T (Tr1) cells are characterized by the expression of IL-10 but not FOXP3 and are prominent in chronic infections and following specific immune manipulations in vivo (e.g., peptide immunization or activation by anti-CD3) [97]. Because a lineage-specific transcription factor has yet to be identified for Tr1 cells, and IL-10 is a common cytokine that can be produced by different subsets of CD4⁺ T helper cells (e.g., Th17 cells), it is debatable whether Tr1 cells represent a bona

AHR in Innate-Like Lymphocytes

The role of AHR in ILC3s has been discussed extensively in a previous review [83]. I mainly focus here on the AHR-mediated crosstalk between T cells and ILC3s. RORγt-expressing ILCs (also known as ILC3s) strikingly resemble Th17 and Th22 cells in their cytokine profile (e.g., production of IL-22 and IL-17). Coevolution of two systems may be a fail-safe mechanism to implement redundancy in host immunity to specific infections, especially at mucosal surfaces, and especially during different

Mouse AHR versus Human AHR

Phylogenetic analysis shows that functional orthologs of the Ahr gene are present in mammals, amphibians, reptiles, and birds [120]. Although rodent studies can yield invaluable insights into the function of AHR, particularly in the human immune system, it needs to be kept in mind that there are several differences between the mouse and human AHR pathways that may complicate the interpretation of results. First, a decrease in stability of the human AHR/HSP90 interaction compared to mouse AHR

Translational Considerations Targeting the AHR Pathway

Modulating AHR function offers exciting therapeutic potential in host immunity and inflammation. However, the emerging concept of AHR function in a cell type-specific manner, combined with differences between AHR activation in cell culture in vitro and in animals in vivo, present challenges for targeting the AHR pathway pharmacologically. Therefore, any attempt to activate or inhibit AHR function in vivo using agonists (e.g., ligands) or antagonists (e.g., small-molecule inhibitors) must take

Concluding Remarks

Future research to understand the physiological and pathological role of AHR in the immune system must take into consideration the broad and inducible expression of AHR in various tissues, the elusive nature of its endogenous ligands, and the similarities and differences among cell culture, animal, and human studies (see Outstanding Questions). AHR exerts its function in a context-dependent and very much cell type-specific manner. In vivo studies of AHR function using ligands or other

Acknowledgments

I thank the entire L.Z. laboratory for help and suggestions, and John Bostick for critical reading the manuscript. The work was supported by the National Institutes of Health (AI089954 and DK105562 L.Z.), and by a Cancer Research Institute Investigator Award (LZ). L.Z. is a Pew Scholar in Biomedical Sciences supported by the Pew Charitable Trusts, and an Investigator in the Pathogenesis of Infectious Disease supported by the Burroughs Wellcome Fund.

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Trends in Immunology

Feature ReviewAHR Function in Lymphocytes: Emerging Concepts

Trends

Introduction

Section snippets

AHR Structure and Function

Transcriptional Regulation of AHR Expression

Regulation of AHR Activity

Variety of AHR Ligands

Complex Roles for AHR in T Cell Differentiation

Impact of AHR in Th17 and Th22 Cells

AHR in Treg Cell Development and Function

AHR in Tr1 Development and Function

AHR in Innate-Like Lymphocytes

Mouse AHR versus Human AHR

Translational Considerations Targeting the AHR Pathway

Concluding Remarks

Acknowledgments

Biochem. Biophys. Res. Commun.

Cell

Immunity

J. Biol. Chem.

Trends Immunol.

J. Biol. Chem.

J. Biol. Chem.

Immunity

Immunity

J. Biol. Chem.

Trends Immunol.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophy. Res. Commun.

Immunity

Immunity

Int. Immunopharmacol.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Invest. Dermatol.

Immunity

Cell

Immunity

Immunity

Immunity

Immunity

Immunity

Immunity

Immunity

Immunity

Immunity

Immunity

Immunity

Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor

Proc. Natl. Acad. Sci. U.S.A.

Human Ah receptor cDNA: analysis for highly conserved sequences

Nucleic Acids Res.

Cloning and expression of a human Ah receptor cDNA

Mol. Pharmacol.

The aryl hydrocarbon receptor complex

Annu. Rev. Pharmacol. Toxicol.

AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch

Nat. Immunol.

The aryl hydrocarbon receptor in barrier organ physiology, immunology, and toxicology

Pharmacol. Rev.

The aryl hydrocarbon receptor meets immunology: friend or foe? A little of both

Front. Immunol.

The aryl hydrocarbon receptor: multitasking in the immune system

Annu. Rev. Immunol.

The PAS superfamily: sensors of environmental and developmental signals

Annu. Rev. Pharmacol. Toxicol.

The aryl hydrocarbon receptor: a perspective on potential roles in the immune system

Immunology

Structure and dimerization properties of the aryl hydrocarbon receptor PAS-A domain

Mol. Cell. Biol.

The search for endogenous activators of the aryl hydrocarbon receptor

Chem. Res. Toxicol.

A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors

Proc. Natl. Acad. Sci. U.S.A.

Constitutively active aryl hydrocarbon receptor expressed specifically in T-lineage cells causes thymus involution and suppresses the immunization-induced increase in splenocytes

J. Immunol.

Differential influences of the aryl hydrocarbon receptor on Th17 mediated responses in vitro and in vivo

Feature Review
AHR Function in Lymphocytes: Emerging Concepts