GM-CSF and IL-4 synergistically trigger dendritic cells to acquire retinoic acid-producing capacity

• Published in: International immunology 2009-04, Vol.21 (4), p.361-377
• Main Authors: Yokota, Aya, Takeuchi, Hajime, Maeda, Naoko, Ohoka, Yoshiharu, Kato, Chieko, Song, Si-Young, Iwata, Makoto
• Format: Article
• Language: English
• Subjects: Aldehyde Dehydrogenase - biosynthesis; Aldehyde Dehydrogenase - genetics; Animals; Cells, Cultured; Coculture Techniques; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; fms-Like Tyrosine Kinase 3 - pharmacology; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; gut; homing; Interleukin-13 - pharmacology; Interleukin-4 - pharmacology; Intestines - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Peyer's Patches - immunology; RALDH; Receptors, Interleukin-4 - genetics; Receptors, Interleukin-4 - metabolism; regulatory T; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Th17; Tretinoin - metabolism
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/dxp003

Retinoic acid (RA) produced by intestinal dendritic cells (DCs) imprints gut-homing specificity on lymphocytes and enhances Foxp3+ regulatory T-cell differentiation. The expression of aldehyde dehydrogenase (ALDH) 1A in these DCs is essential for the RA production. However, it remains unclear how the steady-state ALDH1A expression is induced under specific pathogen-free (SPF) conditions. Here, we found that bone marrow-derived dendritic cells (BM-DCs) generated with granulocyte-macrophage colony-stimulating factor (GM-CSF) expressed Aldh1a2, an isoform of Aldh1a, but that fms-related tyrosine kinase 3 ligand-generated BM-DCs did not. DCs from mesenteric lymph nodes (MLN) and Peyer's patches (PP) of normal SPF mice expressed ALDH1A2, but not the other known RA-producing enzymes. Employing a flow cytometric method, we detected ALDH activities in 10–30% of PP-DCs and MLN-DCs. They were CD11chighCD4−/lowCD8αintermediateCD11b−/low F4/80low/intermediateCD45RBlowCD86highMHC class IIhighB220−CD103+. Equivalent levels of aldehyde dehydrogenase activity (ALDHact) and ALDH1A2 expression were induced synergistically by GM-CSF and IL-4 in splenic DCs in vitro. In BM-DCs, however, additional signals via Toll-like receptors or RA receptors were required for inducing the equivalent levels. The generated ALDH1A2+ DCs triggered T cells to express gut-homing receptors or Foxp3. GM-CSF receptor-deficient or vitamin A-deficient mice exhibited marked reductions in the ALDHact in intestinal DCs and the T cell number in the intestinal lamina propria, whereas IL-4 receptor-mediated signals were dispensable. GM-CSF+CD11c−F4/80+ cells existed constitutively in the intestinal tissues. The results suggest that GM-CSF and RA itself are pivotal among multiple microenvironment factors that enable intestinal DCs to produce RA.