1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells

Abstract

1,25-Dihydroxy vitamin D3 (1,25(OH)2D3) is an immunomodulatory agent inducing dendritic cells (DCs) to become tolerogenic. To further understand its mechanisms of action, we have examined the effects of 1,25(OH)2D3 on tolerogenic properties of blood myeloid (M-DCs) and plasmacytoid (P-DCs) human DC subsets. Exposure of M-DCs to 1,25(OH)2D3 up-regulated production of CCL22, a chemokine attracting regulatory T cells, whereas production of CCL17, the other CCR4 ligand, was reduced. 1,25(OH)2D3 also decreased IL-12p75 production by M-DCs, as expected, and inhibited CCR7 expression. 1,25(OH) 2D3 treatment markedly increased CD4+ suppressor T cell activity while decreasing the capacity of M-DCs to induce Th1 cell development. Surprisingly, 1,25(OH)2D3 did not exert any discernible effect on tolerogenic properties of P-DCs, and even their high production of IFN-α was not modulated. In particular, the intrinsically high capacity of P-DCs to induce CD4+ suppressor T cells was unaffected by 1,25(OH)2D3. Both DC subsets expressed similar levels of the vitamin D receptor, and its ligation by 1,25(OH) 2D3 similarly activated the primary response gene cyp24. Interestingly, 1,25(OH)2D3 inhibited NF-κB p65 phosphorylation and nuclear translocation in M-DCs but not P-DCs, suggesting a mechanism for the inability of 1,25(OH)2D3 to modulate tolerogenic properties in P-DCs.