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.
Chuang
Peter I
PI
Department of Medicine, University of Washington, Seattle 98195, USA.
Morefield
Samantha
S
Liu
Chien-Ying
CY
Chen
Stephen
S
Harlan
John M
JM
Willerford
Dennis M
DM
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004742:Enhancer Elements, Genetic; D015321:Gene Rearrangement / Q000187:drug effects; D005803:Genes, Immunoglobulin; D007107:Immune System / Q000187:drug effects; D008223:Lymphoma / Q000139:chemically induced; D051379:Mice; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects; D013950:Thymus Gland / Q000166:cytology; D051020:bcl-X Protein
C096816:BCL2-related protein A1; C494812:Bcl2l1 protein, mouse; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein