Dendritic cell modulation by 1α, 25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro …

MD Griffin, W Lutz, VA Phan… - Proceedings of the …, 2001 - National Acad Sciences
MD Griffin, W Lutz, VA Phan, LA Bachman, DJ McKean, R Kumar
Proceedings of the National Academy of Sciences, 2001National Acad Sciences
Dendritic cells (DCs) play a central role in regulating immune activation and responses to
self. DC maturation is central to the outcome of antigen presentation to T cells. Maturation of
DCs is inhibited by physiological levels of 1α, 25 dihydroxyvitamin D3 [1α, 25 (OH) 2D3] and
a related analog, 1α, 25 (OH) 2-16-ene-23-yne-26, 27-hexafluoro-19-nor-vitamin D3 (D3
analog). Conditioning of bone marrow cultures with 10− 10 M D3 analog resulted in
accumulation of immature DCs with reduced IL-12 secretion and without induction of …
Dendritic cells (DCs) play a central role in regulating immune activation and responses to self. DC maturation is central to the outcome of antigen presentation to T cells. Maturation of DCs is inhibited by physiological levels of 1α,25 dihydroxyvitamin D3 [1α,25(OH)2D3] and a related analog, 1α,25(OH)2-16-ene-23-yne-26,27-hexafluoro-19-nor-vitamin D3 (D3 analog). Conditioning of bone marrow cultures with 10−10 M D3 analog resulted in accumulation of immature DCs with reduced IL-12 secretion and without induction of transforming growth factor β1. These DCs retained an immature phenotype after withdrawal of D3 analog and exhibited blunted responses to maturing stimuli (CD40 ligation, macrophage products, or lipopolysaccharide). Resistance to maturation depended on the presence of the 1α,25(OH)2D3 receptor (VDR). In an in vivo model of DC-mediated antigen-specific sensitization, D3 analog-conditioned DCs failed to sensitize and, instead, promoted prolonged survival of subsequent skin grafts expressing the same antigen. To investigate the physiologic significance of 1α,25(OH)2D3/VDR-mediated modulation of DC maturity we analyzed DC populations from mice lacking VDR. Compared with wild-type animals, VDR-deficient mice had hypertrophy of subcutaneous lymph nodes and an increase in mature DCs in lymph nodes but not spleen. We conclude that 1α,25(OH)2D3/VDR mediates physiologically relevant inhibition of DC maturity that is resistant to maturational stimuli and modulates antigen-specific immune responses in vivo.
National Acad Sciences