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Proc Natl Acad Sci U S A. 2019 May 7;116(19):9511-9520. doi: 10.1073/pnas.1901258116. Epub 2019 Apr 18.

Transcription factors IRF8 and PU.1 are required for follicular B cell development and BCL6-driven germinal center responses.

Author information

1
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; wanghongs@niaid.nih.gov wjl@helix.nih.gov hmorse@niaid.nih.gov.
2
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
3
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
4
Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
5
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
6
Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
7
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; wanghongs@niaid.nih.gov wjl@helix.nih.gov hmorse@niaid.nih.gov.

Abstract

The IRF and Ets families of transcription factors regulate the expression of a range of genes involved in immune cell development and function. However, the understanding of the molecular mechanisms of each family member has been limited due to their redundancy and broad effects on multiple lineages of cells. Here, we report that double deletion of floxed Irf8 and Spi1 (encoding PU.1) by Mb1-Cre (designated DKO mice) in the B cell lineage resulted in severe defects in the development of follicular and germinal center (GC) B cells. Class-switch recombination and antibody affinity maturation were also compromised in DKO mice. RNA-seq (sequencing) and ChIP-seq analyses revealed distinct IRF8 and PU.1 target genes in follicular and activated B cells. DKO B cells had diminished expression of target genes vital for maintaining follicular B cell identity and GC development. Moreover, our findings reveal that expression of B-cell lymphoma protein 6 (BCL6), which is critical for development of germinal center B cells, is dependent on IRF8 and PU.1 in vivo, providing a mechanism for the critical role for IRF8 and PU.1 in the development of GC B cells.

KEYWORDS:

BCL6; IRF8; PU.1; follicular B cells; germinal center

PMID:
31000603
PMCID:
PMC6511064
[Available on 2019-10-18]
DOI:
10.1073/pnas.1901258116

Conflict of interest statement

The authors declare no conflict of interest.

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