REGULATION OF HUMAN B-CELL LYMPHOPOIESIS BY ADHESION MOLECULES AND CYTOKINES

Recent advances in the ability to culture normal human B cell precursors have emphasized the supportive relationship between these cells and stromal cells in the bone marrow microenvironment. It is now possible to examine the role of adhesion molecules and cytokines in the regulation of different stages of human lymphopoiesis using these culture systems. Direct cell-cell adhesion mediated by the integrin adhesion molecule VLA-4 plays a critical role in supporting stromal dependent proliferation of human B cell precursors. In addition, human B precursor cell lines migrate underneath the stromal layer. This transmigration is VLA-4 dependent but not inhibitable by antibody to known VLA-4 ligands. IL-7 is secreted by the stromal layer, and is necessary for stromal-dependent proliferation of early human B cell precursors. Proliferation of early human B cell precursors is inhibited by multiple cytokines, some of which stimulate growth of late B cell precursors or mature B cells. Since the bone marrow stroma is a source of cytokines with B cell precursor growth stimulatory activity, it is possible that adhesion interactions may play a co-stimulatory role with respect to cytokine secretion or response. As the cytokine requirements for human B cell lymphopoiesis become more completely defined, it will be important to uncover the cell-cell signals that regulate lymphophoiesis either directly or through modulation of cytokine secretion by supporting cells in the bone marrow microenvironment. The dependent relationship between human B cell precursors and the bone marrow microenvironment provides a model system for these cell-cell interactions which may be applicable to progenitor development in other lineages.