Expression of CD86 on human marrow CD34+ cells identifies immunocompetent committed precursors of macrophages and dendritic cells

Abstract

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-α (TNF-α generated almost exclusively CD1a+/CD83+ dendritic cells. In contrast, CD34+/CD86- cells cultured in GM-CSF plus TNF-α generated a variety of sell types, including a small population of dendritic cells. In addition, CD34+/CD86+ sells cultured in granulocyte colony-stimulating factor failed to generate CD15+ granulocytes. Therefore, CD34+/CD86+ sells are committed precursors of both macrophages and dendritic cells. The ontogeny of dendritic cells was recapitulated by stimulation of CD34+/CD86- cells with TNF-α that induced expression of CD86. Subsequent costimulation of CD86+ cells with GM-CSF plus TNF-α lead to expression of CD83 and produced terminal dendritic cell differentiation. Thus, expression of CD86 on hematopoietic progenitor sells is regulated by TNF-α and denotes differentiation towards the macrophage or dendritic cell lineages.