Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, the Netherlands.
Eur J Immunol. 2013 Jun;43(6):1608-16. doi: 10.1002/eji.201343325. Epub 2013 Apr 27.
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.
维生素 A 代谢产物视黄酸对于适应性免疫系统的功能很重要，但机制尚不完全清楚。在这里，我们表明维生素 A 对于脾脏中依赖 Notch 的 CD8(-)树突状细胞 (DC) 的生成是必需的。我们观察到 CD8(-)CD4(-)（双阴性 (DN)）和 CD4(+)DC，而不是 CD8(+)DC，表达维生素 A 调节基因。为了确定维生素 A 水平是否影响脾脏 DC 的发育，我们生成了用维生素 A 缺乏饮食喂养的小鼠。我们在用维生素 A 缺乏饮食喂养的小鼠的脾脏中检测到 CD4(+)和 DN DC 的特异性减少，而脾脏和骨髓中的前 DC 数量不受影响。维生素 A 对于 RelB(high)、依赖 Notch 的 CD4(+)和 DN DC 的发育是特异性必需的。此外，DN DC 在维生素 A 缺乏时表现出增殖减少。相比之下，接受富含视黄酸饮食的小鼠显示出依赖 Notch 的 DN DC 的显著扩增。这些数据表明维生素 A 刺激依赖 Notch 的脾脏 DC 的发育，并表明 DC 生成效率低下可能导致维生素 A 缺乏期间观察到的免疫缺陷。
