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

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.