Regulation of Immunoglobulin Light-Chain Recombination by the Transcription Factor IRF-4 and the Attenuation of Interleukin-7 Signaling

Abstract

Productive rearrangement of the immunoglobulin heavy-chain locus triggers a major developmental checkpoint that promotes limited clonal expansion of pre-B cells, thereby culminating in cell-cycle arrest and rearrangement of light-chain loci. By using Irf4-/-Irf8-/- pre-B cells, we demonstrated that two pathways converge to synergistically drive light-chain rearrangement, but not simply as a consequence of cell-cycle exit. One pathway was directly dependent on transcription factor IRF-4, whose expression was elevated by pre-B cell receptor signaling. IRF-4 targeted the immunoglobulin 3′Eκ and Eλ enhancers and positioned a kappa allele away from pericentromeric heterochromatin. The other pathway was triggered by attenuation of IL-7 signaling and activated the iEκ enhancer via binding of the transcription factor E2A. IRF-4 also regulated expression of chemokine receptor Cxcr4 and promoted migration of pre-B cells in response to the chemokine ligand CXCL12. We propose that IRF-4 coordinates the two pathways regulating light-chain recombination by positioning pre-B cells away from IL-7-expressing stromal cells. © 2008 Elsevier Inc. All rights reserved.