The growth response to IL-7 during normal human B cell ontogeny is restricted to B-lineage cells expressing CD34

The growth of human B cell precursors can be supported by bone marrow (BM) stromal cells and IL-7, but the identity of the responding population is unknown. In the current study, we examined the growth characteristics of FACS-purified CD10+/CD34+/cytoplasmic mu- pro-B cells and CD10+/CD34-/cytoplasmic mu+ pre-B cells in an IL-7/BM stromal cell-dependent culture. Our results show that pro-B cells proliferate, whereas pre-B cells do not. Pro-B cell growth was dependent upon direct contact with BM stromal cells, because no growth occurred when pro-B cells were suspended in transwells above a BM stromal cell monolayer in the presence of IL-7. IL-7-stimulated pro-B cells partially differentiated into a pre-B cell population, on the basis of the loss of CD34 and terminal deoxynucleotidyl (TdT) expression, and the acquisition of cytoplasmic mu heavy chains. Examination of platelet endothelial cell adhesion molecule-1/CD31 expression on B cell precursors revealed a bimodal distribution: CD34+ pro-B cells exhibited a high density pattern and CD34- pre-B cells exhibited a low density pattern. The IL-7-induced differentiation of pro-B cells into pre-B cells included a shift from high CD31 to low CD31 expression. Interestingly, pro-B and pre-B cells expressed comparable levels of IL-7R, as determined by flow cytometry, even though pre-B cells were nonresponsive to IL-7 stimulation. Our collective results show that human pro-B cells require both IL-7 and direct contact with BM stromal cells to undergo proliferation and partial differentiation into the pre-B cell stage, whereas pre-B cells are nonresponsive to IL-7 and require other signals for their survival and growth.