An Update on Vitamin D and Human Immunity

Martin Hewison

Disclosures

Clin Endocrinol. 2012;76(3):315-325. 

In This Article

Vitamin D and Adaptive Immunity

Early studies of vitamin D and the immune system demonstrated VDR expression in both T- and B cells.[42] Notably, VDR expression by these cells was only immunologically functional in active, proliferating cells, suggesting an antiproliferative role for 1,25(OH)2D on these cells.[43] T helper (Th) cells appear to be the principal target for 1,25(OH)2D which can suppress Th cell proliferation as well as modulating cytokines production by these cells.[44] Activation of naïve Th cells by antigen in turn leads to the generation of Th subgroups with distinct cytokine profiles: Th1 (IL-2, IFNγ, tumour necrosis factor alpha) and Th2 (IL-3, IL-4, IL-5, IL-10) that respectively support cell-mediated and humoral immunity.[45,46]In vitro 1,25(OH)2D inhibits Th1 cytokines,[47] whilst promoting Th2 cytokines.[48] A third group of Th cells known to be influenced by vitamin D are interleukin-17 (IL-17)-secreting T cells (Th17 cells). Autoimmune disease-susceptible nonobese diabetic (NOD) mice treated with 1,25D exhibit lower levels of IL-17,[49] and 1,25(OH)2D-mediated suppression of murine retinal autoimmunity appears to involve inhibition of Th17 activity.[50] Indeed, recent studies have shown that 1,25(OH)2D suppresses IL-17 production via direct transcriptional suppression of IL-17 gene expression.[51] Another group of T cells known to be potently induced by 1,25(OH)2D are regulatory T cells (Treg).[52] Although part of the Th cell family, Treg act to suppress immune responses by other T cells as part of the machinery to prevent over-exuberant or autoimmune responses.[53] Recent studies have underlined the importance of Tregs in mediating the immunoregulatory actions of vitamin D. Administration of 1,25(OH)2D systemically to patients with renal disease has been shown to expand circulating Treg populations.[54]

Studies of vitamin D and T-cell function have to date focused primarily on the response of these cells to active 1,25(OH)2D. What is less clear is the mechanism by which variations in vitamin D status can also influence T cells, despite reports linking serum levels of 25OHD with specific T-cell populations. For example, circulating levels of 25OHD have been shown to correlate with Treg activity in patients with multiple sclerosis (MS).[55,56] There are four potential mechanisms by which serum 25OHD can influence T-cell function (see Fig. 1): (i) direct effects on T cells mediated via systemic 1,25(OH)2D; (ii) indirect effects on antigen presentation to T cells mediated via localized DC expression of CYP27B1 and intracrine synthesis of 1,25(OH)2D; (iii) direct effects of 1,25(OH)2D on T cells following synthesis of the active form of vitamin D by CYP27B1-expressing monocytes or DCs – a paracrine mechanism; (iv) intracrine conversion of 25OHD to 1,25(OH)2D by T cells. As yet, it is unclear whether one or more of these mechanisms will apply to the regulation of specific T-cell types. For example, the effects of 1,25(OH)2D on Treg can occur indirectly via effects on DCs,[57] but may also involve direct effects on T cells.[58] However, as outlined above, DCs also express CYP27B1[38,59] and may therefore act as the conduit for 25OHD effects on Treg. Interestingly, reports have also described expression of CYP27B1 by T cells,[60] suggesting that 25OHD may also influence the function of these cells via an intracrine mechanism, although the precise relevance of this to specific T-cell types remains unclear.

Despite the fact that expression of VDR by B cells has been recognized for many years,[42] the ability of 1,25(OH)2D to suppress B-cell proliferation and immunoglobulin (Ig) production was initially considered to be an indirect effect mediated via Th cells.[43] However, more recent studies have confirmed direct effects of 1,25(OH)2D on B-cell homoeostasis,[61] with notable effects including inhibition of plasma cell and class switched memory cells differentiation. These effects lend further support for vitamin D's proposed role in B-cell-related autoimmune disorders such as systemic lupus erythamtosus (SLE). Other B-cell targets known to be modulated by for 1,25(OH)2D include IL-10[62] and CCR10,[63] suggesting that the repertoire of B-cell responses to vitamin D extends beyond its effects on B-cell proliferation and Ig synthesis.

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