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J Exp Med. 2015 Apr 6;212(4):539-53. doi: 10.1084/jem.20141380. Epub 2015 Mar 30.

BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms.

Author information

  • 1Division of Hematology and Medical Oncology, Weill Cornell Medical College, Cornell University, New York, NY 10065.
  • 2Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
  • 3University 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.
  • 4Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL 34987.
  • 5Division of Hematology and Medical Oncology, Weill Cornell Medical College, Cornell University, New York, NY 10065 shane@lji.org amm2014@med.cornell.edu.
  • 6Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037 shane@lji.org amm2014@med.cornell.edu.

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.

PMID:
25824819
PMCID:
PMC4387288
DOI:
10.1084/jem.20141380
[PubMed - indexed for MEDLINE]
Free PMC Article
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