Expression of CD86 on human marrow CD34(+) cells identifies immunocompetent committed precursors of macrophages and dendritic cells.
Macrophages and dendritic cells derive from a hematopoietic stem cell and the existence of a common committed progenitor has been hypothesized. We have recently found in normal human marrow a subset of CD34(+) cells that constitutively expresses HLA-DR and low levels of CD86, a natural ligand for the T cell costimulation receptor CD28. This CD34(+) subset can elicit responses from allogeneic T cells. In this study, we show that CD34(+)/CD86(+) cells can also present tetanus toxoid antigen to memory CD4(+) T cells. CD86 is expressed at low levels in macrophages and high levels in dendritic cells. Therefore, we have tested the hypothesis that CD34(+)/CD86(+) cells are the common precursors of both macrophages and dendritic cells. CD34(+)/CD86(+) marrow cells cultured in granulocyte-macrophage colony-stimulating factor (GM-CSF)-generated macrophages. In contrast, CD34(+)/CD86(-) cells cultured in GM-CSF generated a predominant population of granulocytes. CD34(+)/CD86(+) cells cultured in GM-CSF plus tumor necrosis factor-alpha (TNF-alpha) generated almost exclusively CD1a+/CD83(+) dendritic cells. In contrast, CD34(+)/CD86(-) cells cultured in GM-CSF plus TNF-alpha generated a variety of cell types, including a small population of dendritic cells. In addition, CD34(+)/CD86(+) cells cultured in granulocyte colony-stimulating factor failed to generate CD15(+) granulocytes. Therefore, CD34(+)/CD86(+) cells are committed precursors of both macrophages and dendritic cells. The ontogeny of dendritic cells was recapitulated by stimulation of CD34(+)/CD86(-) cells with TNF-alpha that induced expression of CD86. Subsequent costimulation of CD86(+) cells with GM-CSF plus TNF-alpha lead to expression of CD83 and produced terminal dendritic cell differentiation. Thus, expression of CD86 on hematopoietic progenitor cells is regulated by TNF-alpha and denotes differentiation towards the macrophage or dendritic cell lineages.
Ryncarz
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Division of Clinical Research, Fred Hutchinson Cancer Research Center, Division of Oncology, University of Washington, Seattle, WA, USA.
Anasetti
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D017951:Antigen Presentation; D015703:Antigens, CD / Q000096:biosynthesis*; D018949:Antigens, CD1 / Q000096:biosynthesis / Q000235:genetics; D018952:Antigens, CD34 / Q000032:analysis; D051940:B7-2 Antigen; D015415:Biomarkers; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007959:Lymphocyte Culture Test, Mixed; D008264:Macrophages / Q000166:cytology* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013745:Tetanus Toxoid / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015703:Antigens, CD; D018949:Antigens, CD1; D018952:Antigens, CD34; D051940:B7-2 Antigen; D015415:Biomarkers; C497964:CD86 protein, human; D008562:Membrane Glycoproteins; D013745:Tetanus Toxoid; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor