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Proc Natl Acad Sci U S A. 2015 Oct 27;112(43):13324-9. doi: 10.1073/pnas.1507312112. Epub 2015 Oct 12.

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

Author information

  • 1Division of Vaccine Discovery, La Jolla Institute of Allergy and Immunology, La Jolla, CA 92037;
  • 2Center for Integrated Medical Sciences, RIKEN, Yokohama 230-0045, Japan;
  • 3Division of Vaccine Discovery, La Jolla Institute of Allergy and Immunology, La Jolla, CA 92037; Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92037 shane@lji.org.

Abstract

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 the Prdm1 cis-regulatory elements in Tfh cells, Prdm1 expression 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 abrogating Prdm1 expression. In addition to Prdm1, 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.

KEYWORDS:

B-cell help; T follicular helper cells; germinal centers

PMID:
26460037
PMCID:
PMC4629362
DOI:
10.1073/pnas.1507312112
[PubMed - indexed for MEDLINE]
Free PMC Article
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