J. Exp. Med., Volume 188, Number 7, October 5, 1998 1231-1238

Receptor Editing Occurs Frequently during Normal B Cell Development

By Marc W. Retter^* and David Nemazee^*

From the ^* National Jewish Medical and Research Center, Division of Basic Sciences, Department of Pediatrics, Denver, Colorado 80206; and the  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  light chain genes usually rearrange after  genes. This allowed us to analyze  loci in IgM⁺ cells to determine how frequently in-frame  genes fail to suppress  gene rearrangements. To do this, we analyzed recombined VJ genes inactivated by subsequent recombining sequence (RS) rearrangement. RS rearrangements delete portions of the  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  loci, as nearly half (47%) of the RS-inactivated VJ joins were in-frame. These findings suggest that receptor editing occurs at a surprisingly high frequency in normal B cells.

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