Vitamin effects on the immune system: vitamins A and D take centre stage

Abstract

Vitamins are essential constituents of our diet that have long been known to influence the immune system. Vitamins A and D have received particular attention in recent years as these vitamins have been shown to have an unexpected and crucial effect on the immune response. We present and discuss our current understanding of the essential roles of vitamins in modulating a broad range of immune processes, such as lymphocyte activation and proliferation, T-helper-cell differentiation, tissue-specific lymphocyte homing, the production of specific antibody isotypes and regulation of the immune response. Finally, we discuss the clinical potential of vitamin A and D metabolites for modulating tissue-specific immune responses and for preventing and/or treating inflammation and autoimmunity.

Figure 1. Overview of vitamin A and D metabolism

a | Vitamin D₃ (VD₃) is acquired in the diet or synthesized in the skin and hydroxylated in the liver to 25(OH)VD₃, the main circulating form. 25(OH)VD₃ is then hydroxylated in the kidneys by the cytochrome P450 protein CYP27B1 to become 1,25(OH)₂VD₃, the physiologically most active metabolite, which then reaches the blood where it has multiple systemic effects. Cells of the immune system, including macrophages, dendritic cells (DCs), T and B cells express the enzymes CYP27A1 and/or CYP27B1, and therefore can also hydroxylate 25(OH)VD₃ to 1,25(OH)₂VD₃. 1,25(OH)₂VD₃ acts on immune cells in an autocrine or paracrine manner by binding to the vitamin D receptor (VDR). 24-hydroxylase (CYP24A1) catabolizes 1,25(OH)₂VD₃ to its inactive metabolite, calcitroic acid, which is excreted in the bile. b | Vitamin A (also known as retinol) is obtained from the diet and transported in the blood as a complex with retinol-binding protein (RBP) and transthyretin (TTR). In the liver, retinol is esterified to retinyl esters and stored in stellate cells. In other tissues, including gut-associated immune cells, retinol is oxidized to retinal by alcohol dehydrogenases (ADHs) or short chain dehydrogenase/reductases (SDRs). Retinal is then oxidized to all-trans-retinoic acid in an irreversible reaction that is catalysed by retinal dehydrogenases (RALDHs). Retinoic acid acts on immune cells by binding to the retinoic acid receptor (RAR). Retinoic acid is catabolized in the liver and in other tissues by the enzyme CYP26 and its metabolites are eliminated in the bile and urine. c | Retinoid X receptors (RXRs) can form RXR–RAR ( receptor for all-trans- and 9-cis-retinoic acid), RXR–PPARβ (peroxisome-proliferator-activated receptor β)(receptor for fatty acids), RXR–RXR (receptor for 9 cis-retinoic acid), or RXR–VDR (receptor for 1,25(OH)₂VD₃) complexes. The ratio between cellular retinoic acid-binding proteins (CRABPs) and fatty acid-binding protein 5 (FABP5) might determine whether retinoic acid signals through RAR–RXR or PPARβ–RXR, leading to different functional outcomes. RARE, retinoic acid response element; VDRE, VD response element.

Figure 2. Mechanisms of vitamin D immunomodulation

Systemic or locally produced 1,25(OH)₂VD₃ exerts its effects on several immune-cell types, including macrophages, dendritic cells (DCs), T and B cells. Macrophages and DCs constitutively express vitamin D receptor (VDR), whereas VDR expression in T cells is only upregulated following activation. In macrophages and monocytes, 1,25(OH)₂VD₃ positively influences its own effects by increasing the expression of VDR and the cytochrome P450 protein CYP27B1. Certain Toll-like-receptor (TLR)-mediated signals can also increase the expression of VDR. 1,25(OH)₂VD₃ also induces monocyte proliferation and the expression of interleukin-1 (IL-1) and cathelicidin (an antimicrobial peptide) by macrophages, thereby contributing to innate immune responses to some bacteria. 1,25(OH)₂VD₃ decreases DC maturation, inhibiting upregulation of the expression of MHC class II, CD40, CD80 and CD86. In addition, it decreases IL-12 production by DCs while inducing the production of IL-10. In T cells, 1,25(OH)₂VD₃ decreases the production of IL-2, IL-17 and interferon-γ (IFNγ) and attenuates the cytotoxic activity and proliferation of CD4⁺ and CD8⁺ T cells. 1,25(OH)₂VD₃ might also promote the development of forkhead box protein 3 (FOXP3)⁺ regulatory T (T_Reg) cells and IL-10-producing T regulatory type 1 (T_R1) cells. Finally, 1,25(OH)₂VD₃ blocks B-cell proliferation, plasma-cell differentiation and immunoglobulin production. ASCs, antibody-secreting cells.

Figure 3. Effects of vitamin A metabolites on gut mucosal immunity

a | In addition to upregulating the expression of gut-homing receptors, retinoic acid has also been reported to promote T-helper-2 (T_H2)-cell differentiation. Moreover, retinoic acid blocks the differentiation of T helper 17 (T_H17) cells and induces forkhead box protein 3 (FOXP3)⁺regulatory T (T_Reg) cells in the presence of transforming growth factor-β (TGFβ) by reciprocally downregulating receptor-related orphan receptor-γt (RORγt) and inducing FOXP3 expression in T cells, respectively. Retinoic acid also enhances the TGFβ-driven induction of T_Reg cells and induces gut-homing receptor expression in both naturally occurring and induced T_Reg cells. T_H17-cell differentiation requires TGFβ, interleukin-6 (IL-6), IL-23 and, in humans, IL-1β. b | B cells activated in non-mucosal lymphoid tissues, such as peripheral lymph nodes and spleen, mostly become IgG⁺ antibody-secreting cells (ASCs) and home to the bone marrow and sites of inflammation. By contrast, B cells activated in mucosal-associated lymphoid tissues (MALT) give rise to IgA⁺ ASCs. In MALT (including the gut-associated lymphoid tissue; GALT), TGFβ and CD40 ligand (CD40L) are essential for the generation of T-cell-dependent IgA responses, whereas BAFF (B-cell-activating factor) and APRIL (a proliferation-inducing ligand) are important for T-cell-independent IgA responses. APRIL is induced by Toll-like receptor (TLR) signals, commensal flora and thymic stromal lymphopoietin (TSLP). Inducible nitric oxide synthase (iNOS), which is also upregulated by TLR signals and commensal flora, produces nitric oxide (NO), allows proper TGFβ signalling and induces the production of APRIL and BAFF by dendritic cells. Thus, iNOS and NO are essential for both T-cell-dependent and -independent IgA responses. In the GALT, retinoic acid might contribute directly to the differentiation of T-cell-independent (and probably also T-cell-dependent) IgA⁺ ASCs. In addition, retinoic acid might contribute indirectly to T-cell-dependent and -independent IgA responses by inducing iNOS expression.

Figure 4. Roles of retinoic acid and 1,25(OH)₂VD₃ in tissue-specific lymphocyte homing

a | Retinoic acid produced by gut-associated lymphoid tissue (GALT)-resident dendritic cells and probably by other cells, such as intestinal epithelial cells, potently induces the expression of the gut-homing receptors α₄β₇-integrin and CC-chemokine receptor 9 (CCR9) by activated CD4⁺ and CD8⁺ T cells. Retinoic acid also blocks the induction of skin-homing receptors by T cells, including CCR4 and the ligands for E- and P-selectin. Effector and memory T cells exhibit plasticity in their homing commitment: skin-homing T cells can become gut-homing T cells and vice versa if they are restimulated either with or without retinoic acid, respectively. In the presence of interleukin-12 (IL-12), 1,25(OH)₂VD₃ (the main circulating vitamin D₃ (VD₃) metabolite) induces the expression of skin-associated CCR10 by human (but not mouse) T cells. However, 1,25(OH)₂VD₃ blocks the induction of E-selectin ligands and therefore inhibits skin-homing. So, it is possible that 1,25(OH)₂VD₃ induces CCR10 expression after T cells have homed to the skin to retain them in the epidermis (in which the CCR10 ligand CCL27 is expressed). 1,25(OH)₂VD₃ also antagonizes the upregulation of gut-homing receptors, whereas retinoic acid reciprocally blocks the induction of CCR10 expression by 1,25(OH)₂VD₃. b | Like T cells, B cells also exhibit plasticity in their homing commitment and can either acquire or lose gut-homing potential when reactivated with or without retinoic acid, respectively. Retinoic acid induces the expression of α₄β₇-integrin and CCR9 on activated B cells and antibody-secreting cells (ASCs). It is unknown whether retinoic acid alters the homing of B cells and ASCs to other tissues, such as the bone marrow or sites of inflammation. ASCs in mucosal tissues (mostly IgA⁺ ASCs) also express CCR10, although it is unclear where and how this receptor is upregulated by these cells.