Vitamin D and 1,25(OH)2D regulation of T cells

Abstract

Vitamin D is a direct and indirect regulator of T cells. The mechanisms by which vitamin D directly regulates T cells are reviewed and new primary data on the effects of 1,25 dihydroxyvitamin D (1,25(OH)2D) on human invariant natural killer (iNK)T cells is presented. The in vivo effects of vitamin D on murine T cells include inhibition of T cell proliferation, inhibition of IFN-γ, IL-17 and induction of IL-4. Experiments in mice demonstrate that the effectiveness of 1,25(OH)2D requires NKT cells, IL-10, the IL-10R and IL-4. Comparisons of mouse and human T cells show that 1,25(OH)2D inhibits IL-17 and IFN-γ, and induces T regulatory cells and IL-4. IL-4 was induced by 1,25(OH)2D in mouse and human iNKT cells. Activation for 72 h was required for optimal expression of the vitamin D receptor (VDR) in human and mouse T and iNKT cells. In addition, T cells are potential autocrine sources of 1,25(OH)2D but again only 48-72 h after activation. Together the data support the late effects of vitamin D on diseases like inflammatory bowel disease and multiple sclerosis where reducing IL-17 and IFN-γ, while inducing IL-4 and IL-10, would be beneficial.

Figure 1

Fresh peripheral blood mononuclear cells (PBMCs) stimulated with α-Galcer were cultured for 72 h with or without 1,25(OH)₂D treatment and supernatants were analyzed by ELISA for IFN-γ and IL-4 production. n = 10 different PBMC donors. * P < 0.05. Experiments using humans were done with the approval of the Pennsylvania State University, University Park, PA, Institutional Review Board: #32141.

Figure 2

iNKT cell expansion ex vivo. PBMCs were stimulated with 100 ng/mL α-GalCer for 12 days to expand iNKT cells. n = 12 individual donors were used.

Figure 3

Vitamin D receptor (VDR) expression is up regulated with activation. iNKT cell lines were restimulated with α-GalCer and pulsed irradiated PBMCs in vitro. Cells were harvested at 6, 24 and 48 h post stimulation. iNKT cells (gated on CD1d-tet+ cells) were stained with anti-VDR antibodies (Clone H4537, R&D Systems) The isotype control staining is the grey histogram. Data shown is one representative of two experiments performed done with iNKT cell lines from 2 different donors.