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Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation

Nature Immunology volume 10, pages 1193–1199 (2009)Cite this article

Abstract

The location of embryonic lymph node development is determined by the initial clustering of lymphoid tissue–inducer (LTi) cells. Here we demonstrate that both the chemokine CXCL13 and the chemokine CCL21 attracted LTi cells at embryonic days 12.5–14.5 and that initial clustering depended exclusively on CXCL13. Retinoic acid (RA) induced early CXCL13 expression in stromal organizer cells independently of lymphotoxin signaling. Notably, neurons adjacent to the lymph node anlagen expressed enzymes essential for RA synthesis. Furthermore, stimulation of parasymphathetic neural output in adults led to RA receptor (RAR)-dependent induction of CXCL13 in the gut. Therefore, our data show that the initiation of lymph node development is controlled by RA-mediated expression of CXCL13 and suggest that RA may be provided by adjacent neurons.

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Figure 1: Specific migration of LTi cells and precursors toward chemokines.
Figure 2: CXCL13 and CCL21 are present in E13.5 developing lymph nodes.
Figure 3: Lymph node development and CXCL13 expression occur independent of LTβR signaling.
Figure 4: RA induces CXCL13 expression via RARβ.
Figure 5: Raldh2−/− E14.5 embryos lack most lymph node anlagen.
Figure 6: RALDH2 is localized in neurons adjacent to lymph node anlagen.
Figure 7: Stimulation of neurons leads to CXCL13 expression.

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Acknowledgements

We thank animal caretakers for care of the animals; G. Kraal and T. Geijtenbeek for critically reading the manuscript; R. Molenaar for help; H. Kalay for labeling antibodies; D. Littman (Skirball Institute of Biomolecular Medicine), S. Nishikawa (Riken Center for Developmental Biology) and K. van Gisbergen (Academic Medical Center, Amsterdam) for antibodies; and J. van der Meulen (Centraal Bureau voor de Statistiek, The Netherlands) for help with statistical analysis. Supported by the US National Institutes of Health (HL69409 and AI072689 to T.D.R.) and the Netherlands Organization for Scientific Research (VIDI grant 016.096.310 to W.J.d.J.; VICI grant 918.56.612 to R.E.M. and S.A.v.d.P.; and Genomics grant 050-10-120 to R.E.M. and M.F.V.).

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Author notes

  1. Brenda J Olivier, Gera Goverse and Mark F Vondenhoff: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands

    Serge A van de Pavert, Brenda J Olivier, Gera Goverse, Mark F Vondenhoff, Mascha Greuter, Patrick Beke & Reina E Mebius

  2. Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester, Rochester, New York, USA

    Kim Kusser & Troy D Randall

  3. Max Delbrück Center for Molecular Medicine, Berlin, Germany

    Uta E Höpken & Martin Lipp

  4. Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

    Karen Niederreither

  5. Faculty of Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway

    Rune Blomhoff

  6. Department of Experimental Medical Science, Immunology Section, Lund University, Lund, Sweden

    Kasia Sitnik & William W Agace

  7. Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands

    Wouter J de Jonge

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Contributions

S.A.v.d.P., B.J.O., M.F.V., G.G., M.G., W.J.d.J. and P.B. did the experiments and data analysis; K.K. and T.D.R. provided the Cxcl13−/− embryos; U.E.H. and M.L. provided the Cxcr5−/− embryos; K.N. provided the Raldh2−/− embryos; R.B., K.S. and W.W.A. provided the DR5 embryos; S.A.v.d.P. and R.E.M. designed the experiments; S.A.v.d.P., T.D.R., and R.E.M. wrote the manuscript; and R.E.M. directed the study.

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Correspondence to Reina E Mebius.

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van de Pavert, S., Olivier, B., Goverse, G. et al. Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation. Nat Immunol 10, 1193–1199 (2009). https://doi.org/10.1038/ni.1789

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