V-H-gene replacement is a recombination event in which a pre-existing immun
oglobulin heavy chain gene can be altered by the replacement of the rearran
ged V-H gene segment with another V-H gene segment. Although this event has
been demonstrated in various model systems, its role in generating antibod
y diversity is still unsettled. We have used a genetically modified mouse s
train, QM, with a quasi monoclonal primary B cell repertoire specific for N
P to determine whether V-H gene replacement can generate a new antigen spec
ificity. Hybridomas generated from QM splenocytes alter immunization with d
ifferent antigens, gave rise to antibodies with specificity to the immunizi
ng antigen or with new specificities. We found V-H-gene replacement was use
d to change the original heavy chain gene rearrangement specific for NP int
o a heavy chain gene encoding the new antigen specificity. V-H-gene replace
ment intermediates were detected both before and after the immunization, su
ggesting that the event was selective rather than instructive. These result
s demonstrate that V-H-gene replacement can generate a new antibody heavy c
hain gene with a different functional and selectable antigen specificity.