Article abstract
Nature Immunology 9, 917 - 926 (2008)
Published online: 6 July 2008 | doi:10.1038/ni.1632
Identification of regulatory functions for 4-1BB and 4-1BBL in myelopoiesis and the development of dendritic cells
Seung-Woo Lee1, Yunji Park2, Takanori So1, Byoung S Kwon3,5, Hilde Cheroutre2, Robert S Mittler4 & Michael Croft1
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.
- Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA
- Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
- Immunomodulation Research Center, University of Ulsan, Ulsan, Korea, and National Cancer Center, Goyang, Kyonggi-do, Korea.
- Department of Surgery and Emory Vaccine Center, University School of Medicine, Emory University, Atlanta, Georgia 30329, USA.
- Present address: Cell and Immunobiology, and R&D Center for Cancer Therapeutics, National Cancer Center, Ilsan, Gyeonggi-Do, Korea.
Correspondence to: Michael Croft1 e-mail: mick@liai.org
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