Roles of the Ig κ light chain intronic and 3′ enhancers in Igk somatic hypermutation

Somatic hypermutation (SHM) of the rearranged Ig genes is required for the affinity maturation of Abs. SHM is almost exclusively targeted to the rearranged Ig loci, but the mechanism of this gene-specific targeting remains unclear. The Ig kappa L chain locus contains multiple enhancers, including the MAR/intronic (iE(kappa)) and 3' enhancers (3'E-kappa). Previous transgenic studies indicate that both kappa enhancers are individually necessary for SHM of Igk. In contrast, later studies of Ag-selected V-kappa genes in 3'E-kappa(-/-) mice found no absolute requirement for 3'E-kappa in kappa SHM. To address the roles of the two kappa enhancers in SHM in a physiological context, we analyzed SHM of the endogenous Igk in mice with a targeted deletion of either iE(kappa) or 3'E-kappa in Peyer's patch germinal center B cells. Our findings indicate that, although 3'E-kappa is quantitatively important for SHM of Igk, iE(kappa) is not required for kappa SHM. In addition, a reduction of kappa mRNA levels is also detected in activated 3'E-kappa(-/-) B cells. These findings suggest that iE(kappa) and 3'E-kappa play distinct roles in regulating Igk transcription and SHM.