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Langerhans Cell Maturation and Contact Hypersensitivity Are Impaired in Aryl Hydrocarbon Receptor-Null Mice¹

Institut für umweltmedizinische Forschung at the Heinrich-Heine University of Düsseldorf, Düsseldorf, Germany

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported through the German Bundesministerium für Umwelt (Grant BMU.B2).

² Address correspondence and reprint requests to Dr. Charlotte Esser, Institut für umweltmedizinische Forschung, Auf’m Hennekamp 50, 40225 Düsseldorf, Germany. E-mail address: chesser{at}uni-duesseldorf.de

³ Abbreviations used in this paper: LC, Langerhans cell; AhR, aryl hydrocarbon receptor; AhRR, AhR repressor; ARNT, AhR nuclear translocator; BM, bone marrow; BMDC, bone marrow-derived dendritic cell; CHS, contact hypersensitivity; DC, dendritic cell; NQO1, NAD(P)H:quinone oxidoreductase; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; WT, wild type.

⁴ The online version of this article contains supplemental material.