MCB Accepts, published online ahead of print on 19 February 2008

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Mol. Cell. Biol. doi:10.1128/MCB.01946-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A role for interferon regulatory factor 4 in receptor editing

Simanta Pathak, Shibin Ma, Long Trinh, and Runqing Lu^*

Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198 USA

^* To whom correspondence should be addressed. Email: Rlu{at}unmc.edu.

Receptor editing is the primary means through which B cells revise antigen receptors and maintain central tolerance. Previous studies have demonstrated that interferon regulatory factor 4 and 8 (IRF-4,8) promote immunoglobulin light chain rearrangement and transcription at the pre-B stage. Here, the role of IRF-4,8 in receptor editing was analyzed. Our results show that secondary rearrangement is impaired in the IRF-4 but not IRF-8 mutant mice, suggesting that receptor editing is defective in the absence of IRF-4. The role of IRF-4 in receptor editing was further examined in B cell receptor transgenic mice. Our results show that secondary rearrangement triggered by membrane bound antigen is defective in the IRF-4 deficient mice. Our results further reveal that defect in secondary rearrangement is more severe at the immunoglobulin locus than at the locus, indicating that IRF-4 is more critical for the rearrangement. We provide evidence demonstrating that expression of IRF-4 is rapidly induced in immature B cells by self antigen and reconstitution of IRF-4 expression in the IRF-4 mutant immature B cells promotes secondary rearrangement. Thus, our studies identify IRF-4 as a nuclear effector of a BCR signaling pathway that promotes secondary rearrangement at the immature B cell stage.

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