Gene Regulation by 1,25-Dihydroxyvitamin D3 in CD4+CD25+ Cells Is Enabled by IL-2

Vitamin D may be responsible for reducing the development and severity of autoimmune and allergic diseases. Topically applied 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) enhances the immunoregulatory ability of CD4+CD25+ T cells residing in the skin-draining lymph nodes (SDLNs) of mice. The mechanisms responsible were investigated by examining the expression of 84 cytokine and cytokine-related genes in a 96-well gene array. CD4+CD25+ cells isolated from the SDLNs of BALB/c mice, 24 and 96 hours after topical treatment with 1,25(OH)2D3, consistently expressed increased IL-2 mRNA levels and also secreted enhanced quantities of IL-2 after ex vivo stimulation with phorbol 12-myristate 13-acetate and ionomycin. CD4+CD25+ cells from the lymph nodes of naive mice constitutively express the vitamin D receptor, allowing direct modulation by 1,25(OH)2D3. However, in vitro treatment with 1,25(OH)2D3 did not modify the expression of 84 tested cytokine and cytokine-related mRNAs. It was only in the presence of IL-2 that 1,25(OH)2D3 increased the expression of genes including IL-2 and TLR4. Further, 1,25(OH)2D3 enhanced the ability of IL-2 to stimulate CD4+CD25+ cells to proliferate in vitro and also regulate contact hypersensitivity responses on adoptive transfer into naive mice. Therefore, 1,25(OH)2D3 enabled by IL-2 can directly enhance the regulatory potential of CD4+CD25+ T cells to control immune disease.