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 popula tion is unknown. In the current study, we examined the growth characte ristics of FACS-purified CD10(+)/CD34+/cytoplasmic mu(-) pro-B cells a nd 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 dir ect contact with BM stromal cells, because no growth occurred when pro -B cells were suspended in transwells above a BM stromal cell monolaye r in the presence of IL-7. IL-7-stimulated pro-B cells partially diffe rentiated into a pre-B cell population, on the basis of the loss of CD 34 and terminal deoxynucleotidyl (TdT) expression, and the acquisition of cytoplasmic mu heavy chains. Examination of platelet endothelial c ell adhesion molecule-1/CD31 expression on B cell precursors revealed a bimodal distribution: CD34(+) pro-B cells exhibited a high density p attern 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 flo w cytometry, even though pre-B cells were nonresponsive to IL-7 stimul ation. Our collective results show that human pro-B cells require both IL-7 and direct contact with BM stromal cells to undergo proliferatio n and partial differentiation into the pre-B cell stage, whereas pre-B cells are nonresponsive to IL-7 and require other signals for their s urvival and growth.