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

• Published in: Immunity (Cambridge, Mass.) Vol. 28; no. 3; pp. 335 - 345
• Main Authors: Johnson, Kristen, Hashimshony, Tamar, Sawai, Catherine M., Pongubala, Jagan M.R., Skok, Jane A., Aifantis, Iannis, Singh, Harinder
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2008; Elsevier Limited
• Subjects: Animals; B-Lymphocytes - cytology; B-Lymphocytes - immunology; Blotting, Western; Bone marrow; Cell Differentiation - immunology; Cell Movement - immunology; Deoxyribonucleic acid; DNA; Electrophoretic Mobility Shift Assay; Flow Cytometry; Gene expression; Gene Rearrangement, B-Lymphocyte, Light Chain - immunology; Immune system; Immunoprecipitation; In Situ Hybridization, Fluorescence; Interferon Regulatory Factors - immunology; Interferon Regulatory Factors - metabolism; Interleukin-7 - immunology; Interleukin-7 - metabolism; Light; Mice; Mice, Mutant Strains; Migration; MOLIMMUNO; Oligonucleotide Array Sequence Analysis; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Signal Transduction - immunology; Stem Cells - cytology; Stem Cells - immunology; Transcription factors; MOLIMMUNO
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2007.12.019

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.