BATF regulates the expression of Nfil3, Wnt10a and miR155hg for efficient induction of antibody class switch recombination in mice

• Published in: European journal of immunology 2018-09, Vol.48 (9), p.1492-1505
• Main Authors: Morman, Rosemary E., Schweickert, Patrick G., Konieczny, Stephen F., Taparowsky, Elizabeth J.
• Format: Article
• Language: English
• Subjects: Animal models; Animals; B cells; B-Lymphocytes - immunology; Basic-Leucine Zipper Transcription Factors - biosynthesis; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - metabolism; BATF; Cells, Cultured; class switch recombination; Class switching; Clonal deletion; Cytidine Deaminase - genetics; Genes; Heavy chains; Immunoglobulin Class Switching - genetics; Immunoglobulin Isotypes - genetics; Immunoglobulins; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes B; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Transgenic; MicroRNAs - biosynthesis; MicroRNAs - genetics; Nerve Tissue Proteins - biosynthesis; Recombination; signaling pathways; Transcription activation; transcription regulation; Transcriptional Activation - genetics; Wnt Proteins - biosynthesis
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201747360

BATF functions in T cells and B cells to control the host response to antigen and promote the production of class switched immunoglobulins. In this study, we demonstrate that BATF expression increases rapidly, and transiently, following B cell stimulation and use an inducible murine model of BATF deletion to show that this induction is necessary, and sufficient, for immunoglobulin (Ig) class switch recombination (CSR). We examine two genes (Nfil3 and miR155gh) that are positively regulated, and one gene (Wnt10a) that is negatively regulated by BATF during CSR. These genes play essential roles in CSR and each impacts the expression and/or function of the others. Our observations allow these targets of BATF regulation to be positioned in a network upstream of the activation of germline transcripts (GLT) from the IgH locus and of transcriptional activation of Aicda – the gene encoding the enzyme directing Ig gene rearrangements. This work extends the knowledge of the molecular control of CSR and, importantly, positions the induction and function of BATF as an early event in this process. BATF is induced within minutes of B cell stimulation and initiates a program of transcriptional regulation essential for antibody class switch recombination. Three genes are identified as direct targets of BATF. The unique products of these genes function within the network of signaling pathways controlling GLT, AID expression and CSR.