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Identification of regulatory functions for 4-1BB and 4-1BBL in myelopoiesis and the development of dendritic cells

Nature Immunology volume 9, pages 917–926 (2008)Cite this article

Abstract

The costimulatory molecule 4-1BB and its ligand 4-1BBL can control adaptive immunity, but here we show that their interaction also suppressed myelopoiesis. We found that 4-1BBL was expressed on hematopoietic stem cells, differentiating common myeloid progenitors and granulocyte-macrophage progenitors, and 4-1BB was inducible on activated myeloid progenitors. Steady-state numbers of granulocyte-macrophage progenitors, myeloid-lineage cells and mature dendritic cells were higher in 4-1BB- and 4-1BBL-deficient mice, indicative of a negative function, and we confirmed that result with bone marrow chimeras and in vitro, where the absence of interactions between 4-1BB and 4-1BBL led to enhanced differentiation into dendritic cell lineages. The regulatory activity was mediated by 4-1BBL, with binding by 4-1BB inhibiting differentiation of myeloid progenitors. Thus, 4-1BB and 4-1BBL have a previously unknown function in limiting myelopoiesis and the development of dendritic cells.

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Figure 1: Expression of 4-1BBL on hematopoietic stem cells and progenitors.
Figure 2: Enhanced frequency of GMPs and myeloid-lineage cells in the bone marrow and of DCs in the spleen in the absence of the 4-1BB–4-1BBL interaction.
Figure 3: Expression of 4-1BBL and 4-1BB on differentiating myeloid-lineage cells.
Figure 4: Interactions of 4-1BB and 4-1BBL negatively regulate myelopoiesis in vitro.
Figure 5: Myelopoiesis and development of DCs and B cells is limited by 4-1BB.
Figure 6: Enhanced myelopoiesis and development of DCs and B cells in the absence of 4-1BBL.
Figure 7: The accumulation of DCs in the lung is regulated by 4-1BB.
Figure 8: Interactions between 4-1BB and 4-1BBL limit the accumulation of bone marrow–derived DCs.

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Acknowledgements

We thank X. Tang, Y. Adams, Y. Kinjo, W. Xiao, C. Hutter and B. Zhang for technical assistance. Supported by the US National Institutes of Health (AI42944 to M.C.; CA85860 and AI059290 to R.S.M.; AI050265 to H.C.; and EY013325 to B.S.K.), the Arthritis Foundation (B.S.K.), the Diabetes and Immune Disease National Research Institute (S.-W.L.), the Korean Research Foundation (2005-804-E00001 to B.S.K.), the Korean National Cancer Center (0890830-1 to B.S.K.) and the Crohn's and Colitis Foundation of America (Y.P.). This is manuscript 938 from the La Jolla Institute for Allergy and Immunology.

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Author notes

  1. Byoung S Kwon

    Present address: Present address: Cell and Immunobiology, and R&D Center for Cancer Therapeutics, National Cancer Center, Ilsan, Gyeonggi-Do, Korea.,

Authors and Affiliations

  1. Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA,

    Seung-Woo Lee, Takanori So & Michael Croft

  2. Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.,

    Yunji Park & Hilde Cheroutre

  3. Immunomodulation Research Center, University of Ulsan, Ulsan, Korea, and National Cancer Center, Goyang, Kyonggi-do, Korea.,

    Byoung S Kwon

  4. Department of Surgery and Emory Vaccine Center, University School of Medicine, Emory University, Atlanta, Georgia 30329, USA.,

    Robert S Mittler

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Contributions

S.-W.L., Y.P., T.S., R.S.M. and M.C. designed the research and analyzed the data; S.-W.L., Y.P. and T.S. did the experiments at the La Jolla Institute for Allergy and Immunology; S.-W.L. did experiments as a visiting scientist with R.S.M. at Emory University; R.S.M., B.S.K. and H.C. contributed reagents and contributed to the preparation of the manuscript; and S.-W.L. and M.C. wrote the manuscript.

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Correspondence to Michael Croft.

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Lee, SW., Park, Y., So, T. et al. Identification of regulatory functions for 4-1BB and 4-1BBL in myelopoiesis and the development of dendritic cells. Nat Immunol 9, 917–926 (2008). https://doi.org/10.1038/ni.1632

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