Secondary rearrangements and hypermutation generate sufficient B cell diversity to mount protective antiviral immunoglobulin responses.
Variable (V) region gene replacement was recently implicated in B cell repertoire diversification, but the contribution of this mechanism to antibody responses is still unknown. To investigate the role of V gene replacements in the generation of antigen-specific antibodies, we analyzed antiviral immunoglobulin responses of "quasimonoclonal" (QM) mice. The B cells of QM mice are genetically committed to exclusively express the anti-(4-hydroxy-3-nitrophenyl) acetyl specificity. However, approximately 20% of the peripheral B cells of QM mice undergo secondary rearrangements and thereby potentially acquire new specificities. QM mice infected with vesicular stomatitis virus (VSV), lymphocytic choriomeningitis virus, or poliovirus mounted virus-specific neutralizing antibody responses. In general, kinetics of the antiviral immunoglobulin responses were delayed in QM mice; however, titers similar to control animals were eventually produced that were sufficient to protect against VSV-induced lethal disease. VSV neutralizing single-chain Fv fragments isolated from phage display libraries constructed from QM mice showed VH gene replacements and extensive hypermutation. Thus, our data demonstrate that secondary rearrangements and hypermutation can generate sufficient B cell diversity in QM mice to mount protective antiviral antibody responses, suggesting that these mechanisms might also contribute to the diversification of the B cell repertoire of normal mice.
López-Macías
C
C
Institute of Experimental Immunology, Department of Pathology, University Hospital, CH-8091 Zürich, Switzerland.
Kalinke
U
U
Cascalho
M
M
Wabl
M
M
Hengartner
H
H
Zinkernagel
R M
RM
Lamarre
A
A
D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000235:genetics; D000916:Antibody Diversity; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D015322:Gene Rearrangement, B-Lymphocyte; D018390:Gene Targeting; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009500:Neutralization Tests; D012689:Sequence Homology, Nucleic Acid; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology
D000914:Antibodies, Viral; D004247:DNA