Receptor Editing Occurs Frequently during Normal B Cell Development By Marc

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 l light chain genes usually rearrange after k genes. This allowed us to analyze k loci in IgM l 1 cells to determine how frequently in-frame k genes fail to suppress l gene rearrangements. To do this, we analyzed recombined V k J k genes inactivated by subsequent recombining sequence (RS) rearrangement. RS rearrangements delete portions of the k 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 k loci, as nearly half (47%) of the RS-inactivated V k J k joins were in-frame. These findings suggest that receptor editing occurs at a surprisingly high frequency in normal B cells.