Charlotte Esser

Natural Aryl Hydrocarbon Receptor Ligands Control Organogenesis of Intestinal Lymphoid Follicles

Nutrients can shape immune system development function through aryl hydrocarbon receptor signaling. Innate lymphoid cells (ILC) expressing the transcription factor RORγt induce the postnatal formation of intestinal lymphoid follicles and regulate intestinal homeostasis. RORγt+ ILC express the aryl hydrocarbon receptor (AhR), a highly conserved, ligand-inducible transcription factor believed to control adaptation of multicellular organisms to environmental challenges. We show that AhR is required for the postnatal expansion of intestinal RORγt+ ILC and the formation of intestinal lymphoid follicles. AhR activity within RORγt+ ILC could be induced by dietary ligands such as those contained in vegetables of the family Brassicaceae. AhR-deficient mice were highly susceptible to infection with Citrobacter rodentium, a mouse model for attaching and effacing infections. Our results establish a molecular link between nutrients and the formation of immune system components required to maintain intestinal homeostasis and resistance to infections.

The aryl hydrocarbon receptor in immunity.

Low-molecular-weight chemicals or xenobiotics might contribute to the increasing prevalence of allergies and autoimmunity. Certain chemicals can alter immune responses via their action on the cytosolic transcription factor aryl hydrocarbon receptor (AhR). AhR recognizes numerous small xenobiotic and natural molecules, such as dioxin and the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole. Although AhR is best known for mediating dioxin toxicity, knockout studies have indicated that AhR also plays a role in normal physiology, including certain immune responses. In particular, Th17 cells and dendritic cells express high levels of AhR. We review here current evidence for the physiological role of AhR in the immune system, focussing in particular on T-cell biology.

The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology

The aryl hydrocarbon receptor (AhR) is an evolutionarily old transcription factor belonging to the Per-ARNT-Sim–basic helix-loop-helix protein family. AhR translocates into the nucleus upon binding of various small molecules into the pocket of its single-ligand binding domain. AhR binding to both xenobiotic and endogenous ligands results in highly cell-specific transcriptome changes and in changes in cellular functions. We discuss here the role of AhR for immune cells of the barrier organs: skin, gut, and lung. Both adaptive and innate immune cells require AhR signaling at critical checkpoints. We also discuss the current two prevailing views—namely, 1) AhR as a promiscuous sensor for small chemicals and 2) a role for AhR as a balancing factor for cell differentiation and function, which is controlled by levels of endogenous high-affinity ligands. AhR signaling is considered a promising drug and preventive target, particularly for cancer, inflammatory, and autoimmune diseases. Therefore, understanding its biology is of great importance.

Langerhans Cell Maturation and Contact Hypersensitivity Are Impaired in Aryl Hydrocarbon Receptor-Null Mice

Langerhans cells (LC) are professional APCs of the epidermis. Recently, it was suggested that they are tolerogenic and control adverse immune reactions, including against low molecular mass chemicals. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is involved in low molecular mass chemical metabolism and cell differentiation. Growing evidence suggests a role for the AhR in the immune system, for example, by influencing dendritic cell and T cell differentiation. We found that the AhR and its repressor AhRR are expressed in LC of C57BL/6 mice. LC, unexpectedly, did not respond to a strong AhR agonist with induction of transcripts of xenobiotic metabolizing enzymes. To test for a physiological role of the AhR in LC, we investigated how AhR deficiency affects LC. We found that AhR-deficient LC were impaired in maturation; they remained smaller and less granular, did not up-regulate expression of costimulatory molecules CD40, CD80, and CD24a during in vitro maturation, and their phagocytic capacity was higher. Interestingly, the mRNA expression of tolerogenic Ido was severely decreased in AhR-deficient LC, and enzyme activity could not be induced in AhR-deficient bone marrow-derived dendritic cells. GM-CSF, needed for LC maturation, was secreted in significantly lower amounts by AhR-deficient epidermal cells. Congruent with this impaired maturity and capacity to mature, mice mounted significantly weaker contact hypersensitivity against FITC. Our data suggest that the AhR is involved in LC maturation, both cell autonomously and through bystander cells. At the same time, the AhR might be part of the risk strategy of LC against unwanted immune activation by potential skin allergens.

IDENTIFICATION OF DIOXIN-RESPONSIVE ELEMENTS (DRES) IN THE 5' REGIONS OF PUTATIVE DIOXIN-INDUCIBLE GENES

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an exogenous ligand for the cytosolic aryl hydrocarbon receptor (AhR), a ligand-inducible transcription factor whose exact physiological role remains elusive. TCDD has been shown to modulate the expression of a large array of genes, albeit often indirectly, by demonstration of protein or mRNA upregulation. Here, by computer analysis of available promoter sequences, we identify dioxin-responsive elements in the promoter regions of many putative AhR regulated and therefore dioxin-inducible genes.

Aryl Hydrocarbon Receptor Is Critical for Homeostasis of Invariant γδ T Cells in the Murine Epidermis

An immunoregulatory role of aryl hydrocarbon receptor (AhR) has been shown in conventional αβ and γδ T cells, but its function in skin γδ T cells (dendritic epidermal T cells [DETC]) is unknown. In this study, we demonstrate that DETC express AhR in wild-type mice, and are specifically absent in the epidermis of AhR-deficient mice (AhR-KO). We show that DETC precursors are generated in the thymus and home to the skin. Proliferation of DETC in the skin was impaired in AhR-KO mice, resulting in a >90% loss compared with wild type. Surprisingly, DETC were not replaced by αβ T cells or conventional γδ T cells, suggesting a limited time frame for seeding this niche. We found that DETC from AhR-KO mice failed to express the receptor tyrosine kinase c-Kit, a known growth factor for γδ T cells in the gut. Moreover, we found that c-kit is a direct target of AhR, and propose that AhR-dependent c-Kit expression is potentially involved in DETC homeostasis. DETC are a major source of GM-CSF in the skin. Recently, we had shown that impaired Langerhans cell maturation in AhR-KO is related to low GM-CSF levels. Our findings suggest that the DETCs are necessary for LC maturation, and provide insights into a novel role for AhR in the maintenance of skin-specific γδ T cells, and its consequences for the skin immune network.

The aryl hydrocarbon receptor (AHR), a novel regulator of human melanogenesis.

Skin cancer, chloracne and hyperpigmentation have been associated with the exposure to environmental contaminants such as polychlorinated biphenyls, dioxins or polycyclic aromatic hydrocarbons. These compounds are xenobiotic high‐affinity ligands for the aryl hydrocarbon receptor (AHR), a ligand‐activated transcription factor with important physiological roles in, for example, the control of cell proliferation and inflammation. We show here that exposure of normal human melanocytes to the most potent dioxin, 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD), results in activation of the AHR signaling pathway and an AHR‐dependent induction of tyrosinase activity, the key enzyme of the melanogenic pathway. In accordance with the upregulation of tyrosinase enzyme activity, total melanin content was also elevated in TCDD‐exposed melanocytes. Neither the induction of tyrosinase enzyme activity or of total melanin could be attributed to enhanced cell proliferation, but was rather due to the induction of tyrosinase and tyrosinase‐related protein 2 gene expression. Thus, the AHR is able to modulate melanogenesis by controlling the expression of melanogenic genes.

The Murine IL-2 Promoter Contains Distal Regulatory Elements Responsive to the Ah Receptor, a Member of the Evolutionarily Conserved bHLH-PAS Transcription Factor Family

Signaling through the TCR and costimulatory signals primarily control transcription of the IL-2 gene in naive T cells. The minimal promoter necessary for this expression lies proximal, between −300 and the transcription start site. We had previously shown that activation of the arylhydrocarbon receptor (AHR), a member of the bHLH-PAS family of transcription factors, leads to increased mRNA expression of IL-2 in murine fetal thymocytes. The AHR is abundant in the thymus and may play a role for the development of the immune system. Moreover, its overactivation by chemicals such as dioxins leads to immunosuppression and thymic involution. Binding motifs for the liganded AHR can be identified in the distal region −1300 to −800 of the mouse IL-2 promoter. We show here that these DNA motifs, the so-called dioxin response elements, after binding to the liganded AHR are sufficient to transactivate luciferase expression in a reporter gene system. The IL-2 gene can be induced by the AHR also in thymocytes in vivo after injection of 2,3,7,8-tetrachlorodibenzo-p-dioxin, a potent ligand of the AHR. The AHR mediates the IL-2 induction as shown with AHR-deficient mice. However, in spleen cells in vitro costimulation via the TCR is necessary for optimal IL-2 gene induction. Thus, the IL-2 promoter region contains novel distal regulatory elements that can be addressed by the AHR to induce IL-2 and can cooperate with the proximal promoter in this.

Functions of the aryl hydrocarbon receptor in the skin

Among other functions, the skin serves as the barrier against the environment and provides vital protection from physical or chemical harm and from infection. Skin cells express the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor and sensor of environmental chemicals; at the same time, AHR ligands are abundant in skin from exogenous or endogenous sources. For example, solar radiation, in particular ultraviolet (UV) B, generates AHR ligands from tryptophan in the skin. Recent evidence has shown that AHR is involved in the (patho)physiology of skin including the regulation of skin pigmentation, photocarcinogenesis, and skin inflammation. We here provide a state-of-the-art summary of work which relates to the role of the AHR in (1) adaptive responses against environmental challenges such as UVB or topical chemicals and (2) intrinsic developmental roles for homeostasis of skin cells and (3) skin immunity. We also discuss the existing evidence that AHR antagonists or AHR ligands may be used for the prevention and/or treatment of skin disease.

Ultraviolet B radiation-induced immunosuppression: molecular mechanisms and cellular alterations

About 30 years ago, the discovery of the connection between UV radiation and the immune system triggered the field of photoimmunology. In that time, many aspects were studied, and a complex picture emerged. UV absorption results in multi-tiered molecular and cellular UV radiation-induced events, eventually affecting the immune system. The shorter wavelengths of the UV spectrum, i.e. UVB appear to be the most critical players for impairing immune reactions. This review summarizes and discusses UVB radiation-induced effects on the skin, considering the primary efferent molecular events following energy absorption of UVB radiation, ending with the various afferent cellular changes, such as induction of regulatory T cells.