Research highlights

Immune regulation: Vitamin D₃ promotes immune function in the skin

Nature Reviews Immunology 7, 174-175 (March 2007) | doi:10.1038/nri2047

The importance of vitamins for optimal health has been known for a long time, but two recent papers reveal a previously unknown role for vitamin D₃ in regulating immune responses in the skin.

In the first study, researchers from Richard Gallo's group investigated the regulation of molecules that help to combat infection during wound healing. Their work had previously shown that expression of the antimicrobial peptide cathelicidin increases during wound healing and that cathelicidin expression can be induced in keratinocytes in vitro by vitamin D₃. Vitamin D₃ is generated as an inactive form in the skin in response to sunlight and is converted to the active form, 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), by an enzymatic cascade involving 25-hydroxylases and 1-hydroxylase.

In their current work, Gallo and colleagues observed that the expression of Toll-like receptor 2 (TLR2) and the TLR cofactor CD14 are also induced in wounds and in vitro by vitamin D₃. Furthermore, they observed an increase in the expression of 1-hydroxylase in response to transforming growth factor- (TGF). Inactive vitamin D₃ was converted to its active form following exposure of keratinocytes to TGF. In turn, activation of vitamin D₃ led to the expression of cathelicidin, TLR2 and CD14, therefore explaining how these innate immune molecules are induced following injury. The increase in TLR2 expression allows keratinocytes to respond to microbial stimulation and also generates an amplification loop: TLR2 signalling leads to increased expression of 1-hydroxylase, and therefore more production of active vitamin D₃, which induces the expression of cathelicidin and enhances the expression of TLR2.

In the second study, from Eugene Butcher's group, the researchers investigated how epidermal tropism is imprinted on T cells in the skin. Vitamin A is known to be processed to retinoic acid by mucosal dendritic cells (DCs), which induces the expression of CC-chemokine receptor 9 (CCR9) on gut-homing T cells and therefore allows them to migrate in response to the intestinal CC-chemokine ligand 25 (CCL25). On the basis of this knowledge the authors proposed that vitamin D₃ might have a similar role in influencing epidermal tropism of skin T cells. CCL27 is a skin-specific chemokine ligand expressed by keratinocytes in the epidermis, and the expression of its receptor CCR10 allows T cells to migrate towards this chemokine. The expression of CCR10 was induced by adding active vitamin D₃ to naive T cells in the presence of plate-bound T-cell-activating antibodies specific for CD3 and CD28. CCR10 expression was further enhanced in the presence of interleukin-12, a cytokine produced by Langerhans cells and keratinocytes in the skin. Furthermore, active vitamin D₃ suppressed the expression of the gut-homing receptors ₄₇-integrin and CCR9 by T cells.

So, how is the inactive vitamin D₃ that is generated by sunlight processed to the active form that leads to CCR10 expression? Gene expression analysis of skin DCs showed that they express both 25-hydroxylases and 1-hydroxylase and could produce active vitamin D₃ and induce CCR10 expression on T cells when they were cultured with inactive vitamin D₃.

These two studies reveal that vitamin D₃ can influence both innate and adaptive immune responses in the skin.

Author: Elaine Bell

© 2007 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.