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,25-Dihydroxyvitamin D3 Inhibits Differentiation, Maturation, Activation, and Survival of Dendritic Cells Leading to Impaired Alloreactive T Cell Activation
Roche Milano Ricerche, Milan, Italy
1
,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-
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- 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.
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