Perturbation of B-cell development in mice overexpressing the Bcl-2 homolog A1

Decisions about cell survival or death are central components of adaptive immunity and occur at several levels in immune system development and function. The Bcl-2 family of homologous proteins plays an important role in these decisions in lymphoid cells. Bcl-2, Bcl-xL, and A1 are differentially expressed during B- and T-cell development, and they have shared and distinct roles in regulating cell death. We sought to gain insight into the role of A1 in immune system development and function. A murine A1-a transgene was expressed under the control of the Emu enhancer, and mice with A1 overexpression in B- and T-cell lineages were derived. Thymocytes and early B cells in Emu-A1 mice showed extended survival. B-lineage development was altered, with expansion of the pro-B cell subset at the expense of pre-B cells, suggesting an impairment of the pro- to pre-B-cell transition. This early B-cell phenotype resembled Emu-Bcl-xL mice but did not preferentially rescue cells with completed V(D)J rearrangements of the immunoglobulin heavy chain. In contrast to Emu-Bcl-2 transgenes, A1 expression in pro-B cells did not rescue pre-B-cell development in SCID mice. These studies indicate that A1 protects lymphocytes from apoptosis in vitro but that it has lineage- and stage-specific effects on lymphoid development. Comparison with the effects of Bcl-2 and Bcl-xL expressed under similar control elements supports the model that antiapoptotic Bcl-2 homologs interact differentially with intracellular pathways affecting development and apoptosis in lymphoid cells.