Regulation of VH Replacement by B Cell Receptor–Mediated Signaling in Human Immature B Cells

V H replacement provides a unique RAG-mediated recombination mechanism to edit nonfunctional IgH genes or IgH genes encoding self-reactive BCRs and contributes to the diversification of Ab repertoire in the mouse and human. Currently, it is not clear how V H replacement is regulated during early B lineage cell development. In this article, we show that cross-linking BCRs induces V H replacement in human EU12 μHC + cells and in the newly emigrated immature B cells purified from peripheral blood of healthy donors or tonsillar samples. BCR signaling–induced V H replacement is dependent on the activation of Syk and Src kinases but is inhibited by CD19 costimulation, presumably through activation of the PI3K pathway. These results show that V H replacement is regulated by BCR-mediated signaling in human immature B cells, which can be modulated by physiological and pharmacological treatments.