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International Immunology Advance Access originally published online on February 3, 2009
International Immunology 2009 21(4):361-377; doi:10.1093/intimm/dxp003
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© The Author 2009. Published by Oxford University Press on behalf of The Japanese Society for Immunology. All rights reserved.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press and The Japanese Society for Immunology are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

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

Aya Yokota1,2, Hajime Takeuchi1,2, Naoko Maeda1, Yoshiharu Ohoka1,2, Chieko Kato3, Si-Young Song2,3 and Makoto Iwata1,2

1 Laboratory of Biodefense Research, Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki-shi, Kagawa 769-2193, Japan
2 Japan Science and Technology Agency, CREST, 5 Sanbancho, Chiyoda-ku, Tokyo 102-0075, Japan
3 Institute of Neuroscience, Tokushima Bunri University, 1314-1 Shido, Sanuki-shi, Kagawa 769-2193, Japan

Correspondence to: M. Iwata; E-mail: iwatam{at}kph.bunri-u.ac.jp

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–/lowCD8{alpha}intermediateCD11b–/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.

Keywords: gut, homing, RALDH, regulatory T, Th17

Transmitting editor: M. Miyasaka

Received 29 August 2008, accepted 7 January 2009.


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