IFN regulatory factor 4 and 8 promote Ig light chain κ locus activation in pre-B cell development

Shibin Ma, Anna Turetsky, Long Trinh, Runqing Lu

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Abstract

Previous studies have shown that B cell development is blocked at the pre-B cell stage in IFN regulatory factor (IRF)4 (pip) and IRF8 (IFN consensus sequence binding protein) double mutant mice (IRF4,8-/-). In this study, the molecular mechanism by which IRF4,8 regulate pre-B cell development was further investigated. We show that IRF4,8 function in a B cell intrinsic manner to control pre-B cell development. IRF4,8-/- mice expressing a Bcl-2 transgene fail to rescue pre-B cell development, suggesting that the defect in B cell development in IRF4,8-/- mice is not due to a lack of survival signal. IRF4,8-/- pre-B cells display a high proliferation index that may indirectly inhibit the L chain rearrangement. However, forced cell cycle exit induced by IL-7 withdrawal fails to rescue the development of IRF4,8-/- pre-B cells, suggesting that cell cycle exit by itself is not sufficient to rescue the development of IRF4,8-/- pre-B cells and that IRF4,8 may directly regulate the activation of L chain loci. Using retroviral mediated gene transduction, we show that IRF4 and IRF8 function redundantly to promote pre-B cell maturation and the generation of IgM+ B cells. Molecular analysis indicates that IRF4, when expressed in IRF4,8-/- pre-B cells, induces κ germline transcription, enhances V(D)J rearrangement activity at the κ locus, and promotes L chain rearrangement and transcription. Chromatin immunoprecipitation assay further reveals that IRF4 expression leads to histone modifications and enhanced chromatin accessibility at the κ locus. Thus, IRF4,8 control pre-B cell development, at least in part, by promoting the activation of the κ locus.

Original languageEnglish (US)
Pages (from-to)7898-7904
Number of pages7
JournalJournal of Immunology
Volume177
Issue number11
Publication statusPublished - Dec 1 2006

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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