BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms

• Published in: The Journal of experimental medicine Vol. 212; no. 4; pp. 539 - 553
• Main Authors: Hatzi, Katerina, Nance, J Philip, Kroenke, Mark A, Bothwell, Marcella, Haddad, Elias K, Melnick, Ari, Crotty, Shane
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 06-04-2015
• Subjects: Amino Acid Motifs; B-Lymphocytes - cytology; B-Lymphocytes - immunology; Binding Sites; Cell Differentiation - genetics; Cell Differentiation - immunology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; Female; Humans; Male; Proto-Oncogene Proteins c-bcl-6; STAT Transcription Factors - genetics; STAT Transcription Factors - immunology; T-Lymphocytes, Helper-Inducer - cytology; T-Lymphocytes, Helper-Inducer - immunology; Transcription Factor AP-1 - genetics; Transcription Factor AP-1 - immunology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20141380

Follicular helper T cells (Tfh cells) are required for T cell help to B cells, and BCL6 is the defining transcription factor of Tfh cells. However, the functions of BCL6 in Tfh cells have largely remained unclear. Here we defined the BCL6 cistrome in primary human germinal center Tfh cells to assess mechanisms of BCL6 regulation of CD4 T cells, comparing and contrasting BCL6 function in T and B cells. BCL6 primarily acts as a repressor in Tfh cells, and BCL6 binding was associated with control of Tfh cell migration and repression of alternative cell fates. Interestingly, although some BCL6-bound genes possessed BCL6 DNA-binding motifs, many BCL6-bound loci were instead characterized by the presence of DNA motifs for AP1 or STAT. AP1 complexes are key positive downstream mediators of TCR signaling and external stimuli. We show that BCL6 can directly bind AP1, and BCL6 depends on AP1 for recruitment to BCL6-binding sites with AP1 motifs, suggesting that BCL6 subverts AP1 activity. These findings reveal that BCL6 has broad and multifaceted effects on Tfh biology and provide insight into how this master regulator mediates distinct cell context-dependent phenotypes.