Arylhydrocarbon receptor (AhR) and UVR-induced immunosuppression
Final Report Abstract
Ultraviolet radiation (UVR) suppresses the immune system via the induction of regulatory T cells (Treg). Since these cells act in an antigen-specific fashion, they harbor therapeutic potential. UVR-induced DNA damage has been recognized as the major molecular trigger in this process since reduction of DNA damage by enhanced repair prevents the compromise to the immune system by UVR. Nevertheless, other signaling events may be also involved. Since any UVR effect including the induction of Treg is associated with the generation of DNA damage which basically is the basis for carcinogenesis, we are interested to identify other routes to induce such cells without causing DNA damage. The aryl hydrocarbon receptor (AhR) was identified as another target for UVR since UVR activates the AhR and certain UVR effects were not detected in AhR-deficient cells. In this project, we initially studied whether the AhR is involved in UVR-induced immunosuppression and whether similar effects can be induced by AhR agonists. The AhR antagonist 3-methoxy-4-nitroflavone reduced UVR-mediated immunosuppression and the induction of Treg in the model of murine contact hypersensitivity (CHS). Conversely, activation of the AhR by the agonist 4-nonylphenol (NP) suppressed the induction of CHS and induced antigen-specific Treg similar to UVR. This was further confirmed in AhR knock-out mice in which UVR- as well as NP-induced immunosuppression was significantly reduced. Together, this indicated that the AhR is involved in mediating UVR-induced immunosuppression. Antigen-presenting cells are critically involved in AhR-induced immunosuppression since injection of hapten-coupled dendritic cells (DC) treated with NP into mice did not result in sensitization but induced Treg. NP induced the release of IL-2 by DC which subsequently triggered the release of IL-10. NP upregulated the negative regulatory molecule B7-H4 via the release of IL-2 which was functionally relevant since inhibition of B7-H4 prevented the induction of Treg. Together, this indicated that activation of the AhR switches antigen-presenting cells from a stimulatory into a regulatory phenotype, ultimately inducing Treg. In addition, we studied whether NP can also directly affect T cells. Exposure of CD4+CD25- nonregulatory T cells to NP induced the regulatory T cell markers Foxp3 and GARP. This was functionally relevant since i.v. injection of these cells inhibited induction of CHS. However, elicitation was not suppressed when injected into sensitized mice. This may due to the fact that NP-treated T cells locate to the lymph nodes (LN) and not to the skin since they express the LN homing receptor CD62L. Stimulation with NP-treated T cells with Langerhans cells downregulated CD62L and induced skin homing receptors, supporting the concept of alteration of homing receptor expression by tissue specific antigen-presenting cells. Accordingly, the CHS response in NP-treated and sensitized mice was only suppressed upon a further epicutaneous hapten boost which presumably stimulates Langerhans cells to migrate into the LN and to drive NP-activated T cells into the periphery. Together, NP appears to be a suitable tool to mitigate inflammatory reactions by modulating T cells. Thus, activation of the AhR might represent an alternative to modulate the immune system in a similar fashion like UVR but without causing the adverse effects of UVR including DNA damage. Via this route, Treg may be induced which act in an antigen-specific fashion. Since we were also successful to educate Treg induced by AhR activation to emigrate into the skin, these cells may harbor therapeutic potential by inducing antigen-specific immunosuppression.
Publications
- The Aryl hydrocarbon receptor is involved in UVR-induced immunosuppression. J Invest Dermatol 2013;133:2763-70
Navid F, Bruhs A, Schuller W, Fritsche E, Krutmann J, Schwarz T, Schwarz A
(See online at https://doi.org/10.1038/jid.2013.221) - Activation of the Arylhydrocarbon Receptor Causes Immunosuppression Primarily by Modulating Dendritic Cells. J Invest Dermatol 2015;135:435-44
Bruhs A, Haarmann-Stemmann T, Frauenstein K, Krutmann J, Schwarz T, Schwarz A
(See online at https://doi.org/10.1038/jid.2014.419) - Prevention and mitigation of experimental autoimmune encephalomyelitis by murine β-defensins via induction of regulatory T cells. J Invest Dermatol 2016;136:173-81
Bruhs A, Schwarz T, Schwarz A
(See online at https://doi.org/10.1038/JID.2015.405) - The AHR represses nucleotide excision repair and apoptosis and contributes to UV-induced skin carcinogenesis. Cell Death Differ 2018;25:1823-36
Pollet M, Shaik S, Mescher M, Frauenstein K, Tigges J, Braun SA, Sondenheimer K, Kaveh M, Bruhs A, Meller S, Homey B, Schwarz A, Esser C, Douki T, Vogel CFA, Krutmann J, Haarmann-Stemmann T
(See online at https://doi.org/10.1038/s41418-018-0160-1)
