Influence of immunoglobulin heavy- and light-chain expression on B-cell differentiation.
To study the influence of immunoglobulin heavy-chain (HC) and light-chain (LC) expression in promoting B-cell differentiation, we have introduced functional immunoglobulin HC and/or LC transgenes into the recombinase activating gene-2-deficient background (RAG-2-/-). RAG-2-/- mice do not undergo endogenous V(D)J rearrangement events and, therefore, are blocked in B- and T-cell development at the early pro-B- and pro-T-cell stages. Introduction of immunoglobulin HC transgenes into the RAG-2-/- background promotes the development of a B-lineage cell population that phenotypically has the characteristics of pre-B cells. We have shown further that this population has altered growth characteristics as measured by interleukin-7 responsiveness in culture. Bone marrow cells from immunoglobulin HC transgenic RAG-2-/- mice have up-regulated expression of germ-line kappa LC gene transcripts and down-regulated expression of lambda 5 surrogate LCs (SLCs). Although mu HC/SLC complexes are detectable intracellularly in HC/RAG-2-/- pre-B-cell populations, HC expression is not readily detectable on the surface of these cells. lambda LC RAG-2-/- mice had a bone marrow B-lineage cell phenotype indistinguishable from that of RAG-2-/- littermates, indicating that LC expression by itself has no influence on pro-B cell differentiation. Strikingly, simultaneous introduction of mu HC and lambda LC transgenes into RAG-2-/- mice led to the generation of a substantial population of "monoclonal" peripheral B-cells that were functional with regard to immunoglobulin secretion, indicating that T cells or diverse immunoglobulin repertoires are not necessary for peripheral B-cell development.
Young
F
F
Howard Hughes Medical Institute, Children's Hospital, Boston, Massachusetts 02115.
Ardman
B
B
Shinkai
Y
Y
Lansford
R
R
Blackwell
T K
TK
Mendelsohn
M
M
Rolink
A
A
Melchers
F
F
Alt
F W
FW
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D001854:Bone Marrow Cells; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D015870:Gene Expression; D005803:Genes, Immunoglobulin; D007145:Immunoglobulin kappa-Chains / Q000096:biosynthesis / Q000235:genetics*; D007148:Immunoglobulin mu-Chains / Q000096:biosynthesis / Q000235:genetics*; D015851:Interleukin-7 / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D011506:Proteins / Q000235:genetics
D004268:DNA-Binding Proteins; D007145:Immunoglobulin kappa-Chains; D007148:Immunoglobulin mu-Chains; D015851:Interleukin-7; D011506:Proteins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2