DEVELOPMENTAL REGULATION OF THE BCL-2-PROTEIN AND SUSCEPTIBILITY TO CELL-DEATH IN B-LYMPHOCYTES

Cell death is a prominent feature of B cell development. For example, a large population of B cells dies at the pre-B cell stage presumably due to the failure to express a functional immunoglobulin receptor. In addition, developing B cells expressing antigen receptors for self ar e selectively eliminated at the immature B cell stage. The molecular s ignals that control B cell survival are largely unknown. The product o f the bcl-2 protooncogene may be involved as its overexpression inhibi ts apoptotic cell death in a variety of biological systems. However, t he physiological role of the endogenous Bcl-2 protein during B cell de velopment is undetermined. Here we show a striking developmental regul ation of the Bcl-2 protein in B lymphocytes. Bcl-2 is highly expressed in CD43+ B cell precursors (pro-B cells) and mature B cells but downr egulated at the pre-B and immature B cell stages of development. We fo und that Bcl-2 expressed by B cells is a long-lived protein with a hal f-life of approximately 10 h. Importantly, susceptibility to apoptosis mediated by the glucocorticoid hormone dexamethasone is stage-depende nt in developing B cells and correlates with the levels of Bcl-2 prote in. Furthermore, expression of a bcl-2 transgene rescued pre-B and imm ature B cells from dexamethasone-induced cell death, indicating that B cl-2 can inhibit the apoptotic cell death of progenitors and early B c ells. Taken together, these findings argue that Bcl-2 is a physiologic al signal controlling cell death during B cell development.