Transcription factors IRF8 and PU.1 are required for follicular B cell development and BCL6-driven germinal center responses
Journal Title
Proceedings of the National Academy of Sciences of the United States of America
Publication Type
Journal Article in press
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.
Publisher
NAS
WEHI Research Division(s)
Immunology
PubMed ID
31000603
NHMRC Grants
NHMRC/1054925 NHMRC/1058238
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2019-04-26 10:14:46
Last Modified: 2019-04-26 02:11:09
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