Blimp-1 controls plasma cell function through the regulation of immunoglobulin secretion and the unfolded protein response

Julie Tellier; Wei Shi; Martina Minnich; Yang Liao; Simon Crawford; Gordon K Smyth; Axel Kallies; Meinrad Busslinger; Stephen L Nutt

doi:10.1038/ni.3348

Blimp-1 controls plasma cell function through the regulation of immunoglobulin secretion and the unfolded protein response

Nat Immunol. 2016 Mar;17(3):323-30. doi: 10.1038/ni.3348. Epub 2016 Jan 18.

Authors

Julie Tellier^{1

2}, Wei Shi^{1

3}, Martina Minnich⁴, Yang Liao^{1

2}, Simon Crawford⁵, Gordon K Smyth^{1

6}, Axel Kallies^{1

2}, Meinrad Busslinger⁴, Stephen L Nutt^{1

2}

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
² Department of Medical Biology, The University of Melbourne, Parkville, Australia.
³ Department of Computing and Information Systems, The University of Melbourne, Parkville, Australia.
⁴ Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria.
⁵ School of BioSciences, The University of Melbourne, Parkville, Australia.
⁶ Department of Mathematics and Statistics, The University of Melbourne, Parkville, Australia.

PMID: 26779600
PMCID: PMC4757736
DOI: 10.1038/ni.3348

Abstract

Plasma cell differentiation requires silencing of B cell transcription, while it establishes antibody-secretory function and long-term survival. The transcription factors Blimp-1 and IRF4 are essential for the generation of plasma cells; however, their function in mature plasma cells has remained elusive. We found that while IRF4 was essential for the survival of plasma cells, Blimp-1 was dispensable for this. Blimp-1-deficient plasma cells retained their transcriptional identity but lost the ability to secrete antibody. Blimp-1 regulated many components of the unfolded protein response (UPR), including XBP-1 and ATF6. The overlap in the functions of Blimp-1 and XBP-1 was restricted to that response, with Blimp-1 uniquely regulating activity of the kinase mTOR and the size of plasma cells. Thus, Blimp-1 was required for the unique physiological ability of plasma cells that enables the secretion of protective antibody.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 6 / genetics
Activating Transcription Factor 6 / immunology
Animals
Cell Differentiation / immunology*
Cell Size
Chromatin Immunoprecipitation
DNA-Binding Proteins / genetics
DNA-Binding Proteins / immunology
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Gene Expression Profiling
Gene Expression Regulation
High-Throughput Nucleotide Sequencing
Immunoglobulins / immunology*
Immunoglobulins / metabolism
Interferon Regulatory Factors / genetics
Interferon Regulatory Factors / immunology*
Mice
Mice, Knockout
Microscopy, Electron, Transmission
Plasma Cells / immunology*
Plasma Cells / metabolism
Positive Regulatory Domain I-Binding Factor 1
Regulatory Factor X Transcription Factors
Sequence Analysis, DNA
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / immunology
Transcription Factors / genetics
Transcription Factors / immunology*
Unfolded Protein Response / genetics
Unfolded Protein Response / immunology*
X-Box Binding Protein 1

Substances

Activating Transcription Factor 6
Atf6 protein, mouse
DNA-Binding Proteins
Immunoglobulins
Interferon Regulatory Factors
Prdm1 protein, mouse
Regulatory Factor X Transcription Factors
Transcription Factors
X-Box Binding Protein 1
Xbp1 protein, mouse
interferon regulatory factor-4
Positive Regulatory Domain I-Binding Factor 1
mTOR protein, mouse
TOR Serine-Threonine Kinases

Grants and funding

291740/ERC_/European Research Council/International