Bcl6 middle domain repressor function is required for T follicular helper cell differentiation and utilizes the corepressor MTA3

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 43; pp. 13324 - 13329
• Main Authors: Nance, J. Philip, Bélanger, Simon, Johnston, Robert J., Hu, Joyce K., Takemori, Toshitada, Crotty, Shane
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 27.10.2015; National Acad Sciences
• Subjects: Animals; Biological Sciences; Cell adhesion & migration; Cell Differentiation - immunology; Cellular biology; Chromatin Immunoprecipitation; Cloning, Molecular; DNA Primers - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; Flow Cytometry; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutagenesis, Site-Directed; Neoplasm Proteins - genetics; Neoplasm Proteins - immunology; Positive Regulatory Domain I-Binding Factor 1; Protein expression; Protein Structure, Tertiary; Proto-Oncogene Proteins c-bcl-6; Real-Time Polymerase Chain Reaction; Repressor Proteins - immunology; T-Lymphocytes, Helper-Inducer - immunology; Transcription factors; Transcription Factors - metabolism; B-cell help; germinal centers; T follicular helper cells
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1507312112

T follicular helper (Tfh) cells are essential providers of help to B cells. The transcription factor B-cell CLL/lymphoma 6 (Bcl6) is a lineage-defining regulator of Tfh cells and germinal center B cells. In B cells, Bcl6 has the potential to recruit distinct transcriptional corepressors through its BTB domain or its poorly characterized middle domain (also known as RDII), but in Tfh cells the roles of the Bcl6 middle domain have yet to be clarified. Mimicked acetylation of the Bcl6 middle domain (K379Q) in CD4 T cells results in significant reductions in Tfh differentiation in vivo. Blimp1 (Prdm1) is a potent inhibitor of Tfh cell differentiation. Although Bcl6 K379Q still bound to thePrdm1 cis-regulatory elements in Tfh cells,Prdm1expression was derepressed. This was a result of the failure of Bcl6 K379Q to recruit metastasis-associated protein 3 (MTA3). The loss of Bcl6 function in Bcl6 K379Q-expressing CD4 T cells could be partially rescued by abrogatingPrdm1expression. In addition toPrdm1, we found that Bcl6 recruits MTA3 to multiple genes involved in Tfh cell biology, including genes important for cell migration, cell survival, and alternative differentiation pathways. Thus, Bcl6 middle domain mediated repression is a major mechanism of action by which Bcl6 controls CD4 T-cell fate and function.