014 The arylhydrocarbon receptor agonist 4-n-nonylphenol switches non-regulatory T cells into a regulatory phenotype

Abstract

4-n-nonylphenol (NP), an arylhydrocarbon receptor (AhR)-agonist, was found to inhibit the induction of contact hypersensitivity (CHS) in mice via induction of regulatory T cells (Treg). Although dendritic cells were identified as one of the major targets for NP in its immunosuppressive features, it is unknown whether NP can directly affect T cells as well. To address this issue, non-regulatory T cells (CD4+CD25-) were isolated from trinitrochlorobenzene (TNCB)-sensitized mice and stimulated with NP or left untreated. After 48 hours cells were injected intravenously into naïve recipients which were sensitized after injection; Treg (CD4+CD25+) served as a control. Ear challenge with TNCB was significantly suppressed in mice injected with NP-treated cells comparable to the Treg control. In contrast, injection of untreated CD4+CD25- did not affect CHS in the recipients. Flow cytometry analysis revealed a strong induction of the Treg markers Foxp3 and Garp in response to NP, suggesting that NP shifts non-regulatory T cells into a regulatory phenotype. However, NP-Treg did not suppress the elicitation phase of CHS since the ear challenge response was not suppressed upon intravenous injection of NP-Treg into already sensitized mice. When injected subcutaneously into the ears of sensitized mice before challenge the ear swelling response was significantly reduced, indicating that NP-Treg upon intravenous injection may migrate into the lymph nodes but not into the skin. This may be due to the expression of specific tissue homing receptors. To prove whether NP induces Treg also in the human system CD4+CD25- cells were isolated from peripheral blood mononuclear cells, incubated with NP and subjected to an in vitro suppression assay. NP-Treg suppressed the proliferative capacity of the responder cells, whereas unstimulated CD4+CD25- did not. Together this implies that activation of the AhR switches non-regulatory T cells into a regulatory phenotype which is functionally suppressive.