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Recombinase-Activating Gene-2 of Mice with Altered Expression of IL-7 and Content of Precursor B Cells in Bone Marrow Lymphopoiesis : Apoptosis and Bcl-2 / Bax Regulation of Cell Survival During B

P recursor B cells differentiating in mouse bone marrow (BM) 3 undergo a rigorous selection process that eliminates many functionless and potentially harmful cells (1– 4). A large fraction of B lineage cells is thus diverted into an apoptotic cell death pathway at critical steps in their development. Factors that may contribute to the survival of selected cells include the expression of IgM and associated molecules, microenvironmental interactions with BM stroma, and the expression of apoptosis-regulatory proteins. However, the particular combination of factors normally operating in vivo and their mode of action in mediating B cell selection are as yet largely unresolved. The development and survival of precursor B cells depend upon the generation of IgM and other components of the B cell Ag receptor complex (BCR) (2, 3). Early precursor B cells rearrange ␮ heavy (H) chain genes under the influence of recombinase-activating genes (RAG-1, RAG-2) and terminal deoxynucleotidyl transferase. Productive rearrangement of V H D H J H gene segments leads to expression of ␮-chains both in the cytoplasm (c␮) and, together with surrogate light (L) chains, as cell surface receptors. Following subsequent rearrangement of L chain genes, surface IgM (sIgM) is expressed as part of the BCR. Three phenotypic stages of B cell development can thus be defined by stages in IgM expression (5, 6): 1) pro-B cells, lacking ␮-chains both intracel-lularly and at the cell surface, but displaying B lineage-associated molecules including B220 (CD45RA); 2) pre-B cells, expressing c␮ and transient ␮-containing pre-BCR, but not IgM; and 3) B lymphocytes, displaying sIgM that increases in intensity with further maturation (5). A variety of cell surface markers has been correlated with these three differentiation compartments (6, 7). Cells that successfully execute this genetic program leave BM as functional B lymphocytes. However, many precursor B cells having nonproductive Ig H chain gene rearrangements, other errors of recombination, or the use of D-proximal V H genes with defective expression of pre-BCR (8) undergo apoptosis and are rapidly removed by resident BM macrophages, especially at the pro-B/pre-B cell transition (1, 4, 9). Cells abort completely at this differentiation stage if entirely unable to rearrange Ig H chain genes, as in RAG-deficient mice (10). The rate of apoptosis among precursor B cells in RAG-deficient mice, representing zero cell survival, consequently affords a model by which to measure cell death fractions in other experimental systems. Interactions with local stromal cells and their …