Figure 2.

Sunshine, vitamin D3 and T cell epidermotropism. (a) Model of sunlight-induced T cell epidermotropism in the context of cutaneous antigenic stimulation and DC imprinting of skin T cell trafficking. Sunlight generates vitamin D3 locally in the skin. UVB rays, which penetrate only the outer layers of skin, generate previtamin D3 from 7-dehydrocholesterol, a precursor that is expressed at uniquely high concentrations in the basal epidermis. Over hours to days, the previtamin undergoes spontaneous isomerization to vitamin D3. DCs express the vitamin D3 hydroxylases CYP27A1 and CYP27B1 and, along with keratinocytes, can metabolize the UVB-induced vitamin to its active form, 1,25(OH)₂D3. In the sun-exposed skin, antigen-presenting DCs therefore generate and present high concentrations of 1,25(OH)₂D3 to memory or effector T cells, which respond by upregulating CCR10 and migrating to the keratinocyte-expressed epidermal chemokine CCL27. Cutaneous DCs also migrate through the lymphatics to present antigens to naive T cells in lymph nodes. Many antigen-reactive naive T cells are imprinted with a skin homing phenotype (CLA⁺CCR4^hiα₄β₇–) that directs their trafficking through the blood into the dermis. DC cytokines such as IL-12, which enhances the expression of CLA, are important, but the factors responsible for CCR4 upregulation and, potentially, CCR8 (not shown) expression, and for suppression of α₄β₇ expression, are not understood. After sun exposure, vitamin D3, or locally generated 25(OH)D3 or 1,25(OH)₂D3, may also be transported by DCs or transported bound to transport proteins to the draining lymph node. Vitamin D3 or its metabolites could be presented along with IL-12 and antigen to naive T cells, thus generating an epidermotropic CCR10⁺, skin-homing T cell population in the primary cutaneous immune response. CLA, cutaneous lymphocyte-associated antigen; RXR, retinoid X receptor; VCAM, vascular cell adhesion molecule; VDR, vitamin D receptor. (b) Concentrations of vitamin D and its metabolites found in human skin and blood. The sun provides a skin-specific signal for imprinting of T cell epidermotropism through the local generation of uniquely high levels of vitamin D3. The effective concentrations of vitamin D3 and its metabolites 25(OH) D3 and 1,25(OH)₂D3 needed for inducing CCR10 expression on T cells are shown. The concentrations of vitamin D3 found in the skin are sufficient for DCs to induce CCR10 expression on responding T cells. However, the concentrations of vitamin D and its metabolites in the blood (circulation) and reported D vitamin concentrations in intestines and other tissues are too low for the efficient induction of CCR10 (discussed in ref. 25).