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© The Rockefeller University Press, 0022-1007/1998/10/1231/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 7, October 5, 1998 1231-1238

Articles

Receptor Editing Occurs Frequently during Normal B Cell Development

Marc W. Retter* and David Nemazee*,{ddagger}

From the * National Jewish Medical and Research Center, Division of Basic Sciences, Department of Pediatrics, Denver, Colorado 80206; and the {ddagger} University of Colorado Health Science Center, Department of Immunology, Denver, Colorado 80220

Allelic exclusion is established in development through a feedback mechanism in which the assembled immunoglobulin (Ig) suppresses further V(D)J rearrangement. But Ig expression sometimes fails to prevent further rearrangement. In autoantibody transgenic mice, reactivity of immature B cells with autoantigen can induce receptor editing, in which allelic exclusion is transiently prevented or reversed through nested light chain gene rearrangement, often resulting in altered B cell receptor specificity. To determine the extent of receptor editing in a normal, non-Ig transgenic immune system, we took advantage of the fact that {lambda} light chain genes usually rearrange after {kappa} genes. This allowed us to analyze {kappa} loci in IgM{lambda}+ cells to determine how frequently in-frame {kappa} genes fail to suppress {lambda} gene rearrangements. To do this, we analyzed recombined V{kappa}J{kappa} genes inactivated by subsequent recombining sequence (RS) rearrangement. RS rearrangements delete portions of the {kappa} locus by a V(D)J recombinase-dependent mechanism, suggesting that they play a role in receptor editing. We show that RS recombination is frequently induced by, and inactivates, functionally rearranged {kappa} loci, as nearly half (47%) of the RS-inactivated V{kappa}J{kappa} joins were in-frame. These findings suggest that receptor editing occurs at a surprisingly high frequency in normal B cells.

Key Words: receptor editing • recombining sequence recombination • immune tolerance • B lymphocytes • V(D)J rearrangements

Address correspondence to David Nemazee, The Scripps Research Institute, Mail drop IMM-29, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Phone: 619-784-9528; Fax: 619-784-8805; E-mail: nemazee{at}scripps.edu

Abbreviations used: FWR, framework region; JC{kappa}D/+, heterozygous {kappa} deficient germline genotype; RS, recombining sequence; Tg, transgenic.


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