title: Activation of the arylhydrocarbon receptor causes immunosuppression primarily by modulating dendritic cells.
abstract: UVR suppresses the immune system in an antigen-specific manner via induction of regulatory T cells (Tregs). The specific immunosuppression by UVR harbors therapeutic potential but is associated with UVR-induced DNA damage, requiring the identification of other triggers inducing the same immunosuppressive effects without DNA damage. The aryl hydrocarbon receptor (AhR) was identified as a molecular target for UVR and its activation to be involved in UVR-induced immunosuppression. Accordingly, the AhR agonist 4-n-nonylphenol (NP) suppressed sensitization and induced Treg similar to UVR. Here we show that antigen-presenting cells are critically involved in AhR-induced immunosuppression. Injection of hapten-coupled dendritic cells (DCs) treated with NP into mice did not result in sensitization but induced Treg. NP induced the release of IL-2 by DC that subsequently triggered the release of IL-10. NP upregulated the negative regulatory molecule B7-H4 via the release of IL-2 that was functionally relevant as inhibition of B7-H4 prevented the induction of Treg. Together, this indicates that activation of the AhR switches antigen-presenting cells from a stimulatory into a regulatory phenotype, ultimately inducing Treg. Thus, AhR agonists may represent an alternative to suppress the immune system like UVR but without causing the adverse effects of UVR including DNA damage.
authors.affiliation: Department of Dermatology and Allergology, Kiel University, Kiel, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Bruhs
authors.affiliation: Institut für Umweltmedizinische Forschung (IUF), Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haarmann-Stemmann
authors.affiliation: Institut für Umweltmedizinische Forschung (IUF), Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Frauenstein
authors.affiliation: Institut für Umweltmedizinische Forschung (IUF), Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Jean
authors.initials: J
authors.lastname: Krutmann
authors.affiliation: Department of Dermatology and Allergology, Kiel University, Kiel, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schwarz
authors.affiliation: Department of Dermatology and Allergology, Kiel University, Kiel, Germany. Electronic address: tschwarz@dermatology.uni-kiel.de.
authors.forename: Agatha
authors.initials: A
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000528:radiation effects; D005260:Female; D007108:Immune Tolerance / Q000276:immunology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis; D007376:Interleukin-2 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010636:Phenols; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014466:Ultraviolet Rays / Q000009:adverse effects; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000502:physiology
chemical_list: D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007376:Interleukin-2; D010636:Phenols; D018336:Receptors, Aryl Hydrocarbon; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475824:Vtcn1 protein, mouse; C025256:nonylphenol