Regulation of cell survival during B lymphopoiesis: Apoptosis and Bcl-2/Bax content of precursor B cells in bone marrow of mice with altered expression of IL-7 and recombinase-activating gene-2

B cell development in mouse bone marrow depends critically upon IL-7, To ex amine the possible in vivo trophic role of IL-7, we have quantitated apopto sis and Bcl-2 family proteins in populations of phenotypically defined E li neage cells in IL-7-deficient and IL-7-overexpressing mice. Using immunoflu orescence labeling, multiparameter flow cytometry, and a short-term culture assay, we show that the apoptotic rates of precursor B cells, but not of m ore mature B cells, are enhanced by IL-7 gene deletion, associated with inc reased intracellular content of Bax and decreased Bcl-2, while, conversely, an IL-7 transgene suppresses precursor B cell apoptosis and produces low B ax and high Bcl-2 levels. During normal B cell development, high Bax/Bcl-2 ratios characterize cells undergoing greatest apoptotic cell death. Pro-B c ells in RAG-2(-/-) mice, all destined to abort, show elevated Bar levels an d Bax/Bcl-2 ratios. By comparison with the elevated rate of pro-B cell apop tosis in RAG-2(-/-) mice, provisional estimates have been made for the frac tion of pro-B cells undergoing apoptosis in normal mice (70%), IL-7(-/-) mi ce (85%), and IL-7 transgenic mice (35%), The results demonstrate that IL-7 strongly promotes in vivo cell survival and maintains antiapoptotic Bcl-2/ Bax ratios during the development of precursor B cells in mouse bone marrow .