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CD137 Induces Proliferation of Murine Hematopoietic Progenitor Cells and Differentiation to Macrophages¹

Department of Physiology, and Immunology Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

CD137 is a member of the TNFR family, and reverse signaling through the CD137 ligand, which is expressed as a cell surface transmembrane protein, costimulates or activates APCs. CD137 and CD137 ligand are expressed on small subsets of bone marrow cells. Activation of bone marrow cells through CD137 ligand induces proliferation, colony formation and an increase in cell numbers. Compared with total bone marrow cells, the small subpopulation of progenitor cells that express no lineage markers but express CD117 cells (or Lin^–, CD117⁺ cells) responds with the same activities to CD137 ligand signaling, but at a significantly enhanced rate. Concomitantly to proliferation, the cells differentiate to CFU granulocyte-macrophage and CFU macrophage, and then to monocytes and macrophages but not to granulocytes or dendritic cells. Hematopoietic progenitor cells differentiated in the presence of CD137 protein display enhanced phagocytic activity, secrete high levels of IL-10 but little IL-12 in response to LPS, and are incapable of stimulating T cell proliferation. These data demonstrate that reverse CD137 ligand signaling takes place in hematopoietic progenitor cells, in which it induces proliferation, an increase in cell numbers, colony formation, and differentiation toward monocytes and macrophages.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by grants from the Wilhelm Sander Foundation, Munich, Germany, the National Medical Research Council of Singapore, and the Singapore Stem Cell Consortium.

² Address correspondence and reprint requests to Dr. Herbert Schwarz, Immunology Programme, Centre for Life Sciences 03-05, National University of Singapore, 28 Medical Drive, 117456 Singapore. E-mail address: phssh{at}nus.edu.sg

³ Abbreviations used in this paper: HSC, hematopoietic stem cell; DC, dendritic cell; CFU-GM, CFU granulocyte-macrophage; CFU-M, CFU macrophage; Lin^–, lineage-negative.