Regulation and deletion of early B lineage precursor cells (pro-B cells) in the bone marrow of mice with severe combined immunodeficiency (SCID)

Mice homozygous for the scid (severe combined immunodeficiency) mutation are generally unable to produce B lymphocytes, a condition attributed to defective rearrangements of immunoglobulin genes in precursor B cells. Some early B lineage cells are present in the bone marrow (BM), however. In scid mice, we defined three subsets of early progenitor B cells lacking $ mu$ heavy chains (pro-B cells) based on the expression of terminal deoxynucleotidyl transferase (TdT) and B220 glycoprotein: (a) early (TdT+B220$-$), (b) intermediate (TdT+B220+), and (c) late (TdT$-$B220+). Double immunofluorescence labelling of BM cell suspensions has shown normal numbers of early and intermediate pro-B cells, substantially reduced numbers of late pro-B cells, and an absence of pre-B cells and B cells. Nearly all defective cells, thus, abort at the late pro-B cell stage. Early and intermediate pro-B cells accumulated in metaphase in near-normal numbers after intraperitoneal vincristine administration, apparently not regulated by feedback signals from the B cell pool.The scid mouse provided a system for studies on regulation of pro-B cells and the effectiveness of the deletion mechanism. It was determined that the defective pro-B cells of scid mice were susceptible to the stimulatory effects of an exogenous agent, sheep red blood cells, and a stromal cell-derived growth factor for precursor B cells, interleukin-7, as previously observed in normal mice in vivo. In addition, pro-B cells of scid mice were driven to proliferate by the dysregulated constitutive expression of the c-myc oncogene. In each case, however, all cells aborted soon after reaching the late pro-B stage. Mechanisms by which aberrant cells are deleted from the B lineage, safeguarding against entry of potentially dysregulated cells into the peripheral B cell pool, thus, could not be overwhelmed or evaded by increased proliferative activity of pro-B cells