Interaction between the inhibitory molecule PD-L2 on dendritic cells and repulsive guidance molecule b (RGMb) on lung macrophages is required to establish respiratory tolerance.

inflammatory bowel disease ͉ mucosal immunity ͉ regulatory T cell

No abstract

Low vitamin D status is associated with an increased risk of Th1 mediated autoimmune diseases like inflammatory bowel disease. 1,25(OH) 2 D 3 treatments have been shown to suppress Th1 mediated immunity and protect animals from experimental autoimmunity. Th1 mediated immunity is important for clearance of a number of different infectious diseases. For tuberculosis 1,25(OH) 2 D 3 treatment is associated with decreased Th1 mediated immunity but increased bactericidal activity. Systemic candidiasis is unaffected by 1,25(OH) 2 D 3 treatment. The seemingly paradoxical effects of 1,25(OH) 2 D 3 and vitamin D on Th1 mediated autoimmunity versus infectious immunity point to a broad array of vitamin D targets in the immune system. The interplay of these vitamin D targets and their impact on the host-immune response then dictate the outcome.

Multiple pathways converge to result in the overexpression of T(h)17 cells in the absence of either vitamin D or the vitamin D receptor (VDR). CD4(+) T cells from VDR knockout (KO) mice have a more activated phenotype than their wild-type (WT) counterparts and readily develop into T(h)17 cells under a variety of in vitro conditions. Vitamin D-deficient CD4(+) T cells also overproduced IL-17 in vitro and 1,25 dihydroxyvitamin D(3) inhibited the development of T(h)17 cells in CD4(+) T-cell cultures. Conversely, the induction of inducible (i) Tregs was lower in VDR KO CD4(+) T cells than WT and the VDR KO iTregs were refractory to IL-6 inhibition. Host-specific effects of the VDR were evident on in vivo development of naive T cells. Development of naive WT CD4(+) T cells in the VDR KO host resulted in the overexpression of IL-17 and more severe experimental inflammatory bowel disease (IBD). The increased expression of T(h)17 cells in the VDR KO mice was associated with a reduction in tolerogenic CD103(+) dendritic cells. The data collectively demonstrate that T(h)17 and iTreg cells are direct and indirect targets of vitamin D. The increased propensity for development of T(h)17 cells in the VDR KO host results in more severe IBD.

Vitamin D status changes with season, but the effect of these changes on immune function is not clear. Here we show that in utero vitamin D deficiency in mice results in a significant reduction in iNKT cell numbers that could not be corrected by later intervention with vitamin D or 1,25(OH)2D3 (active form of the vitamin). Furthermore, this was intrinsic to hematopoietic cells as vitamin D deficient bone marrow is specifically defective in generating iNKT cells in wildtype recipients. This vitamin D deficiency induced reduction in iNKT cells is due to increased apoptosis of early iNKT cell precursors in the thymus. While both the VDR and vitamin D regulate iNKT cells, the VDR is required for both iNKT cell function and number, while vitamin D (the ligand) only controls the number of iNKT cells. Given the importance of proper iNKT cell function in health and disease, this prenatal requirement for vitamin D suggests that in humans, the amount of vitamin D available in the environment during prenatal development may dictate the number of iNKT cells and potential risk of autoimmunity.

No abstract

Vitamin D is being touted as an anti-infective agent and it has even been suggested that vitamin D supplementation could be effective against the H1N1 influenza virus. The claims are largely based on the ability of vitamin D to induce antibacterial peptides and evidence that the immune system produces active vitamin D (1,25(OH)2D3) in situ. While there are many examples of immune production of 1,25(OH)2D3 in vitro, there is little in vivo evidence. In addition, it is not clear what role immune production of 1,25(OH)2D3 has on the course of disease. Vitamin D and 1,25(OH)2D3 inhibit T helper type 1 (Th1)/Th17-mediated immune responses and autoimmune diseases by acting on the innate and acquired immune system to inhibit the function of Th1 and Th17 cells. Th1 and Th17 cells are important in host resistance to many infections including tuberculosis (TB) caused by Mycobacterium tuberculosis. Paradoxically the innate immune system is induced to produce antibacterial peptides that are effective against TB in vitro. Data from several models of infection have so far not supported a role for vitamin D in affecting the course of disease. There is also very little evidence that vitamin D affects the course of human TB infection. Experiments have not been done in cells, mice or humans to evaluate the effect of vitamin D on influenza virus. At this time it would be premature to claim that vitamin D has an effect on TB, influenza or any other infection.