The overall objective of this proposal is to test the hypothesis that vitamin A and vitamin D3 and their metabolites help program T cells with specific tissue- and microenvironmental-trafficking properties. Preliminary studies indicate that vitamin A induces gut homing properties on human T cells, as reported in the mouse; and that the skin-specific (sunlight-induced) vitamin D3 induces T cell expression of CC chemokine receptor 10 and chemotaxis to the epidermal chemokine CCL27.
Specific Aims i nclude:
Aim 1 : To determine the role of vitamin D and vitamin A in the induction of trafficking receptors on T cells. The effects of vitamin D and vitamin A (and interactions between them) on homing receptors for skin (CLA, CCR4), the epidermis (CCR10), and the gut will be assessed.
Aim 2 : To characterize the kinetics and regulation of vitamin-dependent and vitamin-independent trafficking receptors on T cells: The kinetics of induction and the reversibility of expression of skin- and gut-associated homing molecules on T cells will be determined. The effects of 1,25(OH)2D3 (the active metabolite of vitamin D) on the generation and homing properties of regulatory T cells will be assessed.
Aim 3 : To test the hypothesis that vitamin D and its nuclear receptor (VDR) control the microenvironmental localization of T cells to the epidermis, and to ask whether vitamin D signaling effects T cell population of the dermis in vivo, in resting or inflamed conditions. Comparison of (CD45 allotype marked) VDR-/- vs wild type T cells in 'competitive' mixed bone marrow chimeras will be used as a sensitive means to assess the effects of UV-generated vitamin D3 and VDR signaling on T cell epidermotropism (distribution to the epidermis within the skin), compared to homing/localization to the dermis (dependent on homing from the blood) in normal or inflamed conditions. T cell trafficking is essential for effective immunity, and is also a target for the control of inflammatory diseases including psoriasis and inflammatory bowel disease. Understanding the regulation of T cell trafficking by local metabolites could lead to novel approaches to the therapy of such diseases, or alternatively to new methods to enhance tissue specific immunity during vaccination. Indeed, vitamin A and vitamin D and drugs related to these vitamins are used to treat various immune and inflammatory diseases already. These studies may shed light on novel cell trafficking-related mechanisms involved. ? ? ?
| Sigmundsdottir, Hekla; Butcher, Eugene C (2008) Environmental cues, dendritic cells and the programming of tissue-selective lymphocyte trafficking. Nat Immunol 9:981-7 |
