Vitamin D-binding protein controls T cell responses to vitamin D

Abstract

BackgroundIn vitro studies have shown that the active form of vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), can regulate differentiation of CD4+ T cells by inhibiting Th1 and Th17 cell differentiation and promoting Th2 and Treg cell differentiation. However, the serum concentration of 1,25(OH)2D3 is far below the effective concentration of 1,25(OH)2D3 found in in vitro studies, and it has been suggested that 1,25(OH)2D3 must be produced locally from the inactive precursor 25-hydroxyvitamin D3 (25(OH)D3) to affect ongoing immune responses in vivo. Although it has been reported that activated T cells express the 25(OH)D-1α-hydroxylase CYP27B1 that converts 25(OH)D3 to 1,25(OH)2D3, it is still controversial whether activated T cells have the capacity to produce sufficient amounts of 1,25(OH)2D3 to affect vitamin D-responsive genes. Furthermore, it is not known how the vitamin D-binding protein (DBP) found in high concentrations in serum affects T cell responses to 25(OH)D3.ResultsWe found that activated T cells express CYP27B1 and have the capacity to produce sufficient 1,25(OH)2D3 to affect vitamin D-responsive genes when cultured with physiological concentrations of 25(OH)D3 in serum-free medium. However, if the medium was supplemented with serum or purified DBP, DBP strictly inhibited the production of 1,25(OH)2D3 and 25(OH)D3-induced T cell responses. In contrast, DBP did not inhibit the effect of exogenous 1,25(OH)2D3. Actin, arachidonic acid and albumin did not affect the sequestration of 25(OH)D3 by DBP, whereas carbonylation of DBP did.ConclusionsActivated T cells express CYP27B1 and can convert 25(OH)D3 to 1,25(OH)2D3 in sufficiently high concentrations to affect vitamin D-responsive genes when cultured in serum-free medium. However, DBP sequesters 25(OH)D3 and inhibits the production of 1,25(OH)2D3 in T cells. To fully exploit the immune-regulatory potential of vitamin D, future studies of the mechanisms that enable the immune system to exploit 25(OH)D3 and convert it to 1,25(OH)2D3in vivo are required.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-014-0035-2) contains supplementary material, which is available to authorized users.

Behind the scenes of vitamin D binding protein: More than vitamin D binding

“…Although T cells express megalin, cubilin expression in naïve T cells is very low and is not upregulated following T cell activation [110]. In comparison with the megalin-mediated endocytosis in mammary cells and kidney cells [53,111], macropinocytosis of 25(OH)-vitamin D 3 -DBP complexes by T cells is not followed by a conversion to 1.25(OH) 2 -vitamin D 3 .…”

“…One or more of the multiple ligands of both players could bridge TSP-1 and CD44, facilitating the DBP binding site complex [99]. receptor, CYP27B1 and the 1,25(OH) 2 -vitamin D 3 -24-hydroxylase CYP24A1 of the cells locally involved in the immune response [110].…”

25-Hydroxyvitamin D serum level in Hashimoto’s thyroiditis, but not Graves’ disease is relatively deficient

“…Immune cells such as monocytes, macrophages, dendritic cells, T-lymphocytes, and B-lymphocytes are targets for the active vitamin D. It has been speculated that vitamin D plays a major role in the regulation of T helper cell differentiation as well as the secretion of TNF-α, IL-4, and IL-17 [6][7][8]. Activated vitamin D regulates T lymphocyte functions by inhibiting the proliferation of Th1 cells and increasing the number of Th2 cells [9]. Vitamin D can suppress Th17 transcription via VDR [10].…”

The Link Between Calcitriol and Anticancer Immunotherapy: Vitamin D as the Possible Balance Between Inflammation and Autoimmunity in the Immune-Checkpoint Blockade

“…In fact, circulating levels of vitamin D are too low to affect immune responses in vivo and immune upregulation by calcitriol is dose dependent [9,10]. Not only antigen presenting cells such as monocytes, macrophages and dendritic cells, but also activated T cells are capable to produce 1,25(OH) 2 D in sufficiently high concentrations to affect vitamin D responsive genes, by binding vitamin D responsive elements.…”

“…In fact, circulating levels of vitamin D are too low to affect immune responses in vivo and immune upregulation by calcitriol is dose dependent [9,10]. Not only antigen presenting cells such as monocytes, macrophages and dendritic cells, but also activated T cells are capable to produce 1,25(OH) 2 triggering of TCR expressed on the surface of naive T cells have the intracellular effect to upregulate VDR, thus enhancing vitamin D signaling and establishing a virtuous circle of T-lymphocyte activation [9].…”