Allelic 'choice' governs somatic hypermutation in vivo at the immunoglobulin κ-chain locus

Shira Fraenkel, Raul Mostoslavsky, Tatiana I. Novobrantseva, Roberta Pelanda, Jayanta Chaudhuri, Gloria Esposito, Steffen Jung, Frederick W. Alt, Klaus Rajewsky, Howard Cedar, Yehudit Bergman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Monoallelic demethylation and rearrangement control allelic exclusion of the immunoglobulin κ-chain locus (Igk locus) in B cells. Here, through the introduction of pre-rearranged Igk genes into their physiological position, the critical rearrangement step was bypassed, thereby generating mice producing B cells simultaneously expressing two different immunoglobulin-κ light chains. Such 'double-expressing' B cells still underwent monoallelic demethylation at the Igk locus, and the demethylated allele was the 'preferred' substrate for somatic hypermutation in each cell. However, methylation itself did not directly inhibit the activation-induced cytidine-deaminase reaction in vitro. Thus, it seems that the epigenetic mechanisms that initially bring about monoallelic variable-(diversity)-joining rearrangement continue to be involved in the control of antibody diversity at later stages of B cell development.

Original languageAmerican English
Pages (from-to)715-722
Number of pages8
JournalNature Immunology
Volume8
Issue number7
DOIs
StatePublished - Jul 2007

Bibliographical note

Funding Information:
We thank I. Keshet for experimental assistance, S. Casola for scientific advice and cell sorting; C. Goettlinger for cell sorting; C. Koenigs, C. Uthoff-Hachenberg and A. Egert for technical help; R. Grützmann (University of Cologne) for anti–mouse k (R33-18.10) and anti-IgM (R33-24.12). Supported by the National Institutes of Health (H.C., K.R. and Y.B.), the Israel Academy of Sciences (Y.B), the German Israel Foundation (Y.B.), the European Community 5th Framework Quality of Life Program (Y.B.), the Israel Cancer Research Fund (H.C.) and the Volkswagen Foundation (K.R.).

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