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

Abstract

1,25-Dihydroxyvitamin D 3 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-γ 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-κB 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.

Systemic Low-Dose UVB Inhibits CD8 T Cells and Skin Inflammation by Alternative and Novel Mechanisms

“…This may be because of the unknown mechanism by which UVB-induced vitamin D 3 in skin can activate regulatory CD4 ϩ CD25 ϩ T cells in sDLNs. 26 Ghoreishi et al 27 observed that regulatory T cells expanded by vitamin D 3 can only inhibit ova-specific CD8 T cells in a local, not a systemic, model. In addition, regulatory T cells may require stimulation by CPD DNA-damaged Langerhans cells migrating into sDLNs, 28 whereas this study found no requirement of CPD formation as a trigger for UVB-induced immunosuppression.…”

“…Compelling evidence from local low-dose UVB models indicates that the proliferation of Ag-specific CD8 T cells to ova protein can be suppressed by regulatory CD4 ϩ CD25 ϩ T cells activated by vitamin D 3 . 27 Modulation of skin dendritic cells by vitamin D 3 is proposed to be important in this process; however, these cells are also prone to UVBinduced CPD. 28 Skin dendritic cells take up exogenous Ag, which they then process and present to CD4 T cells in sDLNs.…”

Topical 1,25‐dihydroxyvitamin D3 subverts the priming ability of draining lymph node dendritic cells

“…10 ). The ability of topical 1,25(OH) 2 D 3 (or analogues) to modify immune responses has been demonstrated in both mice 7,11 and humans, 12,13 where this treatment suppresses contact hypersensitivity responses. Topical 1,25(OH) 2 D 3 may also be effective in controlling allergic diseases including asthma, where subcutaneous immunotherapies incorporating 1,25(OH) 2 D 3 reduce respiratory inflammation during allergic airway disease.…”

“…Administration of 1,25(OH) 2 4,5 and regulatory T cells. 6,7 Skin homing receptors (such as CCR10) can be up-regulated on 1,25(OH) 2 D 3 -stimulated T cells. 8 Topically applied 1,25(OH) 2 D 3 is also an effective treatment for skin inflammatory diseases such as psoriasis.…”

Intradermal application of vitamin D3 increases migration of CD14+dermal dendritic cells and promotes the development of Foxp3+regulatory T cells

“…Compared with T cells induced by LPS-driven crawl-out cells, those induced by LPS/VitD-driven crawl-out cells were significantly more efficient in suppressing bystander T cells as reflected by 30% and expands antigen-specific Treg cells. 26 SC application of VitD was shown to potentiate the regulatory effects of allergenspecific immunotherapy (SIT) in a mouse model of allergic asthma. 9 However, skin contains different DC types-epidermal Langerhans cells (LCs) and CD1a + and CD14 + dermal dendritic cells (DDCs) [27][28][29][30] -and it is unclear to what extent these individual DC types are influenced by VitD.…”