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Expansion of Antigen-Specific Regulatory T Cells with the Topical Vitamin D Analog Calcipotriol¹

Mehran Ghoreishi^*, Paxton Bach^*, Jennifer Obst^*, Mitsuhiro Komba^*, James C. Fleet and Jan P. Dutz^2,*

^* Department of Dermatology & Skin Science and Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; and Purdue University, West Lafayette, IN 47901

1,25-Dihydroxyvitamin D₃ is immunosuppressive both in vivo and in vitro. Topical vitamin D analogs such as calcipotriol alter keratinocyte function, but their effects on cutaneous immune responses are less well understood. We demonstrate that exposure of the skin to calcipotriol before transcutaneous immunization with OVA protein and CpG adjuvant prevents Ag-specific CD8⁺ T cell priming coincident with Langerhans cell depletion in the skin. Immunization through calcipotriol-treated skin induces CD4⁺CD25⁺ regulatory T cells (Treg) that prevent subsequent Ag-specific CD8⁺ T cell proliferation and IFN- production. Treg induced by calcipotriol are able to inhibit the induction and the elicitation of protein contact hypersensitivity. Topical calcipotriol treatment also induces RANKL (receptor activator of NF-B ligand) expression by keratinocytes, a TNF family member involved in modulation of skin dendritic cells. UV light B induces Ag-specific tolerance when it is applied before transcutaneous immunization. We suggest that UV light B-induced tolerance is induced via a vitamin D receptor-dependent mechanism as vitamin D receptor (VDR) knockout mice fail to increase FoxP3⁺ Treg in their peripheral draining lymph node following irradiation. Additionally, keratinocytes of VDR^–/– mice fail to induce RANKL upon UV irradiation or calcipotriol treatment. The in vivo expansion of Ag-specific Treg with the topical application of the vitamin D analog calcipotriol followed by transcutaneous immunization is a simple method to augment functional Ag-specific CD4⁺CD25⁺Foxp3⁺ Treg populations and mimics Ag-specific UV-induced tolerance.

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 work was supported by the Canadian Institutes of Health Research (MOP-81083), Juvenile Diabetes Research Foundation International (Award 4-2004-223), and the Canadian Dermatology Foundation. J.P.D. is a Senior Scholar of the Michael Smith Foundation for Health Research.

² Address correspondence and reprint requests to Dr. Jan P. Dutz, Department of Dermatology & Skin Science, Child and Family Research Institute, University of British Columbia, 835 West Tenth Avenue, Vancouver, British Columbia V5Z 4E8, Canada. E-mail address: dutz{at}interchange.ubc.ca

³ Abbreviations used in this paper: Treg, regulatory T cell; CHS, contact hypersensitivity; DC, dendritic cell; KO, knockout; LC, Langerhans cell; LN, lymph node; VD₃, 1,25-dihydroxyvitamin D₃; RANKL, receptor activator of NF-B ligand; TCI, transcutaneous immunization; VDR, vitamin D receptor.