title: A crucial role for retinoic acid in the development of Notch-dependent murine splenic CD8- CD4- and CD4+ dendritic cells.
abstract: The vitamin A metabolite retinoic acid is important for the function of the adaptive immune system, but the mechanism is not completely understood. Here we show that vitamin A is essential for the generation of Notch-dependent CD8(-) dendritic cells (DCs) in the spleen. We observed that CD8(-) CD4(-) (double negative (DN)) and CD4(+) DCs, but not CD8(+) DCs, express vitamin A regulated genes. To determine whether vitamin A levels influence splenic DC development, we generated mice that were fed a vitamin A-deficient diet. We detected a specific reduction of CD4(+) and DN DCs in the spleens of mice fed a vitamin A-deficient diet, while pre-DC numbers in both spleen and bone marrow were not affected. Vitamin A was specifically necessary for the development of RelB(high) , Notch-dependent CD4(+) , and DN DCs. In addition, DN DCs showed reduced proliferation during vitamin A deficiency. In contrast, mice that had received a diet with increased amounts of retinoic acid showed a significant expansion of Notch-dependent DN DCs. These data demonstrate that vitamin A stimulates the development of Notch-dependent splenic DCs and indicate that inefficient generation of DCs may contribute to the immune deficits observed during vitamin A deficiency.
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Marieke R
authors.initials: MR
authors.lastname: Beijer
authors.forename: Rosalie
authors.initials: R
authors.lastname: Molenaar
authors.forename: Gera
authors.initials: G
authors.lastname: Goverse
authors.forename: Reina E
authors.initials: RE
authors.lastname: Mebius
authors.forename: Georg
authors.initials: G
authors.lastname: Kraal
authors.forename: Joke M M
authors.initials: JM
authors.lastname: den Haan
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology*; D005247:Feeding Behavior; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D051880:Receptors, Notch / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D051841:Transcription Factor RelB / Q000378:metabolism; D014212:Tretinoin / Q000276:immunology*; D014802:Vitamin A Deficiency / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D051880:Receptors, Notch; C497594:Relb protein, mouse; D051841:Transcription Factor RelB; D014212:Tretinoin