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© The Rockefeller University Press, 0022-1007/1999/6/1791/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 11, June 7, 1999 1791-1798

Articles

Secondary Rearrangements and Hypermutation Generate Sufficient B Cell Diversity to Mount Protective Antiviral Immunoglobulin Responses

Constantino López-Macías*, Ulrich Kalinke*, Marilia Cascalho{ddagger}, Matthias Wabl{ddagger}, Hans Hengartner*, Rolf M. Zinkernagel*, and Alain Lamarre*

From the * Institute of Experimental Immunology, Department of Pathology, University Hospital, CH-8091 Zürich, Switzerland; and the {ddagger} Department of Microbiology and Immunology, University of California, San Francisco, California 94143-0670

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, ~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.

Key Words: B cell gene rearrangement • vesicular stomatitis virus • mutation • viral antibodies • antibody diversity

Address correspondence to Constantino López-Macías, Institute of Experimental Immunology, Department of Pathology, University Hospital, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland. Phone: 41-1-255-2989; Fax: 41-1-255-4420; E-mail: ciiirlm{at}pathol.unizh.ch

U. Kalinke's present address is EMBL Mouse Biology Programme, Adriano Buzzati-Traverso Campus, Via E. Ramarini 32, Monterotondo Scalo, I-00016 Rome, Italy.

Abbreviations used: LCMV, lymphocytic choriomeningitis virus; NP, (4-hydroxy-3-nitrophenyl) acetyl; PEG, polyethylene glycol; PV, poliovirus; QM, "quasimonoclonal"; VSV, vesicular stomatitis virus; VSV-IND, VSV Indiana serotype; VSV-G, VSV glycoprotein; scFv, single-chain Fv.


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