A crucial role for retinoic acid in the development of Notch‐dependent murine splenic CD8−CD4− and CD4+ dendritic cells

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.