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.