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Transcription Factor NF-B Regulates Ig Light Chain Gene Rearrangement¹

Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232

The tissue- and stage-specific assembly of Ig and TCR genes is mediated by a common V(D)J recombinase complex in precursor lymphocytes. Directed alterations in the accessibility of V, D, and J gene segments target the recombinase to specific Ag receptor loci. Accessibility within a given locus is regulated by the functional interaction of transcription factors with cognate enhancer elements and correlates with the transcriptional activity of unrearranged gene segments. As demonstrated in our prior studies, rearrangement of the Ig locus is regulated by the inducible transcription factor NF-B. In contrast to the Ig locus, known transcriptional control elements in the Ig locus lack functional NF-B binding sites. Consistent with this observation, the expression of assembled Ig genes in mature B cells has been shown to be NF-B independent. Nonetheless, we now show that specific repression of NF-B inhibits germline transcription and recombination of Ig gene segments in precursor B cells. Molecular analyses indicate that the block in NF-B impairs Ig rearrangement at the level of recombinase accessibility. In contrast, the activities of known Ig promoter and enhancer elements are unaffected in the same cellular background. These findings expand the range of NF-B action in precursor B cells beyond Ig to include the control of recombinational accessibility at both L chain loci. Moreover, our results strongly suggest the existence of a novel Ig regulatory element that is either directly or indirectly activated by NF-B during the early stages of B cell development.

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