title: BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms.
abstract: 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.
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College, Cornell University, New York, NY 10065.
authors.forename: Katerina
authors.initials: K
authors.lastname: Hatzi
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: J Philip
authors.initials: JP
authors.lastname: Nance
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Kroenke
authors.affiliation: University of California, San Diego Department of Surgery and Division of Pediatric Otolaryngology, Rady Children's Hospital-San Diego, San Diego, CA 92123 University of California, San Diego Department of Surgery and Division of Pediatric Otolaryngology, Rady Children's Hospital-San Diego, San Diego, CA 92123.
authors.forename: Marcella
authors.initials: M
authors.lastname: Bothwell
authors.affiliation: Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL 34987.
authors.forename: Elias K
authors.initials: EK
authors.lastname: Haddad
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College, Cornell University, New York, NY 10065 shane@lji.org amm2014@med.cornell.edu.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037 shane@lji.org amm2014@med.cornell.edu.
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
mesh_terms: D020816:Amino Acid Motifs; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D008297:Male; D051560:Proto-Oncogene Proteins c-bcl-6; D050791:STAT Transcription Factors / Q000235:genetics / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000276:immunology
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D050791:STAT Transcription Factors; D018808:Transcription Factor AP-1
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