Physiological concentrations of retinoic acid favor myeloid dendritic cell development over granulocyte development in cultures of marrow cells from mice

Abstract

Differentiation of hematopoietic progenitors to dendritic cells (DCs) is a complex, poorly understood process regulated by cytokines, colony-stimulating factors, growth factor receptors, and transcription factors. However, nutritional factors may play an important role. Vitamin A is essential for proper immune function and is implicated in the development of myeloid lineage cells, especially granulocytes. We investigated the role of vitamin A in the differentiation of myeloid DCs. Cultures of bone marrow cells from mice stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) in medium with reduced serum retinol demonstrated significantly decreased DC development compared with control cultures containing retinol. Surprisingly, granulocytes predominated in cultures stimulated with GM-CSF when retinol was depleted. The addition of all-trans or 9-cis retinoic acid to cultures depleted of retinol significantly restored DCs and inhibited granulocyte development. The DC-promoting effect of vitamin A was specific to myeloid lineage development stimulated by GM-CSF because vitamin A significantly inhibited DC development stimulated by flt-3 ligand. Vitamin A also affected DC major histocompatibility complex (MHC) class II and costimulatory molecule expression. In response to increasing concentrations of vitamin A, the expression of MHC class II decreased on the DC, whereas the expression of costimulatory molecules increased, especially CD86. Our data suggest that vitamin A favors the differentiation of myeloid progenitors to immature myeloid DC instead of granulocytes when dietary vitamin A is adequate, and that vitamin A deficiency may compromise adaptive immune responses that depend on myeloid DC antigen presentation.