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

Int Immunol. 2009 Apr;21(4):361-77. doi: 10.1093/intimm/dxp003. Epub 2009 Feb 3.


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 CD11c(high)CD4(-/low)CD8alpha(intermediate)CD11b(-/low) F4/80(low/intermediate)CD45RB(low)CD86(high)MHC class II(high)B220(-)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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase / biosynthesis*
  • Aldehyde Dehydrogenase / genetics
  • Aldehyde Dehydrogenase 1 Family
  • Animals
  • Cells, Cultured
  • Coculture Techniques
  • Dendritic Cells / drug effects*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Interleukin-13 / pharmacology
  • Interleukin-4 / pharmacology
  • Intestines / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Peyer's Patches / immunology
  • Receptors, Interleukin-4 / genetics
  • Receptors, Interleukin-4 / metabolism
  • Retinal Dehydrogenase
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Tretinoin / metabolism*
  • fms-Like Tyrosine Kinase 3 / pharmacology


  • Interleukin-13
  • Receptors, Interleukin-4
  • Interleukin-4
  • Tretinoin
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Aldehyde Dehydrogenase 1 Family
  • Aldehyde Dehydrogenase
  • Aldh1a2 protein, mouse
  • Retinal Dehydrogenase
  • fms-Like Tyrosine Kinase 3