1α,25-Dihydroxyvitamin D3 Inhibits Differentiation, Maturation, Activation, and Survival of Dendritic Cells Leading to Impaired Alloreactive T Cell Activation

Abstract

1α,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D3, is a potent immunomodulatory agent. Here we show that dendritic cells (DCs) are major targets of 1,25(OH)2D3-induced immunosuppressive activity. 1,25(OH)2D3 prevents the differentiation in immature DCs of human monocytes cultured with GM-CSF and IL-4. Addition of 1,25(OH)2D3 during LPS-induced maturation maintains the immature DC phenotype characterized by high mannose receptor and low CD83 expression and markedly inhibits up-regulation of the costimulatory molecules CD40, CD80, and CD86 and of class II MHC molecules. This is associated with a reduced capacity of DCs to activate alloreactive T cells, as determined by decreased proliferation and IFN-γ secretion in mixed leukocyte cultures. 1,25(OH)2D3 also affects maturing DCs, leading to inhibition of IL-12p75 and enhanced IL-10 secretion upon activation by CD40 ligation. In addition, 1,25(OH)2D3 promotes the spontaneous apoptosis of mature DCs. The modulation of phenotype and function of DCs matured in the presence of 1,25(OH)2D3 induces cocultured alloreactive CD4+ cells to secrete less IFN-γ upon restimulation, up-regulate CD152, and down-regulate CD154 molecules. The inhibition of DC differentiation and maturation as well as modulation of their activation and survival leading to T cell hyporesponsiveness may explain the immunosuppressive activity of 1,25(OH)2D3.

1α,25-Dihydroxyvitamin D3 modulates the murine antibody response to pneumococcal capsular polysaccharide serotype 3 through IL-12

“…Interestingly, we have demonstrated no effect on CD40 expression in our system, in analogy to previous reports [16], while in other systems a suppression of this molecule was observed [17,26]. A common feature of all systems is an almost complete suppression of IL-12 secretion by 1a,25(OH) 2 D 3 [18]. 1a,25(OH) 2 D 3 inhibits polarization into T helper type-1 lymphocytes, either through its inhibitory effect on the IL-12 production of DC, or through a direct effect on naive T lymphocytes (inhibition of IFN-c production, augmentation of IL-4, IL-5, and IL-10 production) [22,23].…”

“…Furthermore, 1a,25(OH) 2 D 3 has profound effects on DC, with strong inhibition of DC maturation and suppression of expression of MHCII, CD80, CD86 and CD83 [18,24,25].…”

“…These effects are believed to be achieved through its action on dendritic cells (DC). 1a,25(OH) 2 D 3 was found to inhibit the IL-12 secretion by DC, and to impair up-regulation of CD80, CD86, CD40, and MHC class II [16][17][18][19].…”

Role of vitamin D in immune responses and autoimmune diseases, with emphasis on its role in multiple sclerosis

“…Vitamin D is responsible for the inhibition of monocyte differentiation into dendritic cells and the inhibition of differentiation, maturation, activation, and survival of dendritic cells, leading to reduced stimulatory activity of dendritic cells on T cells [39,40] . Vitamin D is also important for the interaction of monocytes with T cells, since 1,25(OH) 2 D 3 reduces the CD40L-related production of proinflammatory cytokines such as IL-1 and TNF-.…”

Vitamin D immunoregulation through dendritic cells

“…MoDC generated in the presence of 1,25‐OH‐VD3 were less capable of producing interleukin‐12 (IL‐12) p70,23 but rather secreted IL‐10 14, 24. These cells also possess decreased densities of the co‐stimulatory molecules CD80 and CD86 and of the antigen‐presenting MHCII complex 20, 23. Hence, with all three pillars of T‐cell activation being hampered by 1,25‐OH‐VD3 modulation of moDC development, its potential as a tolerance‐inducing agent for DC therapy, and as a therapeutic immune modulator against diseases with underlying inappropriate or overwhelming inflammation, was recognized 11, 18…”