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Roles of the Ig Light Chain Intronic and 3' Enhancers in Igk Somatic Hypermutation¹

Matthew A. Inlay^2,*, Heather H. Gao^2,*, Valerie H. Odegard, Tongxiang Lin^*, David G. Schatz and Yang Xu^3,*

^* Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093; and Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510

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 L chain locus contains multiple enhancers, including the MAR/intronic (iE) and 3' enhancers (3'E). Previous transgenic studies indicate that both enhancers are individually necessary for SHM of Igk. In contrast, later studies of Ag-selected V genes in 3'E^–/– mice found no absolute requirement for 3'E in SHM. To address the roles of the two enhancers in SHM in a physiological context, we analyzed SHM of the endogenous Igk in mice with a targeted deletion of either iE or 3'E in Peyer’s patch germinal center B cells. Our findings indicate that, although 3'E is quantitatively important for SHM of Igk, iE is not required for SHM. In addition, a reduction of mRNA levels is also detected in activated 3'E^–/– B cells. These findings suggest that iE and 3'E play distinct roles in regulating Igk transcription and SHM.

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