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

BACKGROUND: In vitro studies have shown that the active form of vitamin D(3), 1α,25-dihydroxyvitamin D3 (1,25(OH)(2)D(3)), 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)(2)D(3) is far below the effective concentration of 1,25(OH)(2)D(3) found in in vitro studies, and it has been suggested that 1,25(OH)(2)D(3) must be produced locally from the inactive precursor 25-hydroxyvitamin D3 (25(OH)D(3)) 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)D(3) to 1,25(OH)(2)D(3), it is still controversial whether activated T cells have the capacity to produce sufficient amounts of 1,25(OH)(2)D(3) 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)D(3). RESULTS: We found that activated T cells express CYP27B1 and have the capacity to produce sufficient 1,25(OH)(2)D(3) to affect vitamin D-responsive genes when cultured with physiological concentrations of 25(OH)D(3) in serum-free medium. However, if the medium was supplemented with serum or purified DBP, DBP strictly inhibited the production of 1,25(OH)(2)D(3) and 25(OH)D(3)-induced T cell responses. In contrast, DBP did not inhibit the effect of exogenous 1,25(OH)(2)D(3). Actin, arachidonic acid and albumin did not affect the sequestration of 25(OH)D(3) by DBP, whereas carbonylation of DBP did. CONCLUSIONS: Activated T cells express CYP27B1 and can convert 25(OH)D(3) to 1,25(OH)(2)D(3) in sufficiently high concentrations to affect vitamin D-responsive genes when cultured in serum-free medium. However, DBP sequesters 25(OH)D(3) and inhibits the production of 1,25(OH)(2)D(3) 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)D(3) and convert it to 1,25(OH)(2)D(3)in vivo are required. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12865-014-0035-2) contains supplementary material, which is available to authorized users.