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Vitamin D can be completely synthesized in skin; Study suggests UVB light needed for adequate T-cell programming; New model bypasses liver, kidney hydroxylation
Stanford, Calif.-Vitamin D can be completely synthesized into its active form in the skin,without the involvement of the liver and kidneys,and this process is important to priming T cells towork in the skin,a California researcher says.
The new study by Hekla Sigmundsdottir, Ph.D., a postdoctoral researcher at the Stanford University School of Medicine, also suggests that skin must be exposed to sufficient UVB light to generate adequate programming of T cells to function in the dermis.
Dr. Sigmundsdottir has provided several pieces of an emerging new picture of vitamin D that differs significantly from what was known just a few years ago. The new model places all aspects of formation of the vitamin and its hydroxylation into the active form of 1,25(OH)2 D3 in the skin, and identifies a new and important role for 1,25(OH)2 D3 in immune function.
Dr. Sigmundsdottir has found that dendritic cells can metabolize vitamin D into the active form 1,25(OH)2 D3. Moreover, 1,25(OH)2 D3 provides a mechanism for local cutaneous "imprinting" of responding T cells so that they generate an immune response specific to the microenvironment of the skin.
Using microarray analysis and other techniques, she determined that the genes that are sufficient to hydroxylate vitamin D into its active form are present in dendritic cells and T cells. In culture, only dendritic cells completely expressed the genes that enabled them to fully process vitamin D through both stages of hydroxylation. The last step of that process was present when T cells were co-cultured with dendritic cells.
Parallel research in other labs also recently has demonstrated the capacity of skin cells to produce the completely activated form of vitamin D.
Teasing out the effect of this on immune function required even more complicated research.
Naive T cells do not express the CCR10 receptor, a key receptor that allows them to respond to the skin-specific chemokine CCL27, secreted by keratinocytes, Dr. Sigmundsdottir tells Dermatology Times. But 1,25(OH)2 D3 induces T cells to express the CCR10 receptor.
Her work used several assays, including chemotaxis assays, to show that concentrations of 1,25(OH)2 D3 found in normal serum were insufficient for effective upregulation of CCR10, nor did other compounds such as retinoic acid cause such upregulation. But the generation of 1,25(OH)2 D3 by dendritic cells increased concentration of the molecule in the microenvironment sufficiently to cause that upregulation. The effect was greater with CD8+ cells than with CD4+ cells.
She also determined that 1,25(OH)2 D3 only upregulated CCR10.
"It did not increase the expression of other receptors, such as CCR4, that can mediate T-cell recruitment from blood into the dermis. It also had no effect on receptors used to traffic T cells to lymph nodes, while it inhibited upregulation of receptors that would guide the cells to the gut."
The findings suggest that sunlight-generated vitamin D3 may act mainly on T cells in the skin itself, after the T cells have infiltrated the dermis from the blood, inducing CCR10 to "program" T-cell attraction and retention in the epidermis.
This suggests to Dr. Sigmundsdottir the importance of exposing skin to sufficient UVB light to generate adequate programming of T cells. She acknowledges that the issue is controversial with many dermatologists and notes that such exposure does not have to be lengthy.