Downregulation of FOXP1 is required during germinal center B-cell function

• Published in: Blood 2013-05, Vol.121 (21), p.4311-4320
• Main Authors: Sagardoy, Ainara, Martinez-Ferrandis, Jose I., Roa, Sergio, Bunting, Karen L., Aznar, María Angela, Elemento, Olivier, Shaknovich, Rita, Fontán, Lorena, Fresquet, Vicente, Perez-Roger, Ignacio, Robles, Eloy F., De Smedt, Linde, Sagaert, Xavier, Melnick, Ari, Martinez-Climent, Jose A.
• Format: Article
• Language: English
• Subjects: Animals; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Cell Differentiation - immunology; Cell Line; DNA-Binding Proteins - immunology; DNA-Binding Proteins - metabolism; Down-Regulation - immunology; Forkhead Transcription Factors - immunology; Forkhead Transcription Factors - metabolism; Germinal Center - cytology; Germinal Center - immunology; Humans; Immunobiology; Lymphoma - immunology; Lymphoma - metabolism; Mice; Mice, Transgenic; Palatine Tonsil - cytology; Proto-Oncogene Proteins c-bcl-6; Repressor Proteins - immunology; Repressor Proteins - metabolism; Transcriptional Activation - immunology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-10-462846

B-cell maturation and germinal center (GC) formation are dependent on the interplay between BCL6 and other transcriptional regulators. FOXP1 is a transcription factor that regulates early B-cell development, but whether it plays a role in mature B cells is unknown. Analysis of human tonsillar B-cell subpopulations revealed that FOXP1 shows the opposite expression pattern to BCL6, suggesting that FOXP1 regulates the transition from resting follicular B cell to activated GC B cell. Chromatin immunoprecipitation-on-chip and gene expression assays on B cells indicated that FOXP1 acts as a transcriptional activator and repressor of genes involved in the GC reaction, half of which are also BCL6 targets. To study FOXP1 function in vivo, we developed transgenic mice expressing human FOXP1 in lymphoid cells. These mice exhibited irregular formation of splenic GCs, showing a modest increase in naïve and marginal-zone B cells and a significant decrease in GC B cells. Furthermore, aberrant expression of FOXP1 impaired transcription of noncoding γ1 germline transcripts and inhibited efficient class switching to the immunoglobulin G1 isotype. These studies show that FOXP1 is physiologically downregulated in GC B cells and that aberrant expression of FOXP1 impairs mechanisms triggered by B-cell activation, potentially contributing to B-cell lymphomagenesis. •FOXP1 is downregulated in germinal centers, inversely to BCL6, whereby it regulates a network of genes, half of which are also BCL6 targets.•In transgenic mice, constitutive FOXP1 expression impairs GC formation and function, which might contribute to B-cell lymphomagenesis.