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

Nature Immunology volume 17, pages 323–330 (2016)Cite this article

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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.

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Figure 1: Inactivation of Irf4 and Prdm1 in PCs.
Figure 2: Transcriptional analysis of Blimp-1-deficient PCs.
Figure 3: Blimp-1 controls the size and morphology of PCs.
Figure 4: Blimp-1 controls immunoglobulin production.
Figure 5: Blimp-1 controls the UPR.
Figure 6: Loss of XBP-1 leads to diminished Igh expression and UPR activity.
Figure 7: Blimp-1 regulates the mTOR pathway.

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  • 17 March 2016

    In the version of this article initially published, the label along the vertical axis of the left plot in Figure 3c was incorrect, as was the corresponding text in the legend, and there was an incorrect space between the horizontal axis and curves in the right histogram of Figure 5a. The correct label for Figure 3c is 'ER-Tracker'. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank U. Klein (Columbia University) for Irf4fl/fl mice; L. Glimcher (Weill Cornell Medical College) for Xbp1fl/fl mice; S. Wilcox, M. Chopin and C. Seillet for technical assistance; and J. Leahy for animal care. Supported by the National Health and Medical Research Council of Australia (G.K.S. and S.L.N.; 361646, 575500 and 1054925 to S.L.N.; 1054618 to G.K.S.; 1023454 to G.K.S. and W.S.; and 1049416 to A.K.), the Sylvia and Charles Viertel Foundation (A.K.), the Multiple Myeloma Research Foundation (S.L.N.), Boehringer Ingelheim (Busslinger laboratory) and the European Research Council (291740-LymphoControl for the Busslinger laboratory), and made possible through Victorian State Government Operational Infrastructure Support.

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Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

    Julie Tellier, Wei Shi, Yang Liao, Gordon K Smyth, Axel Kallies & Stephen L Nutt

  2. Department of Medical Biology, The University of Melbourne, Parkville, Australia

    Julie Tellier, Yang Liao, Axel Kallies & Stephen L Nutt

  3. Department of Computing and Information Systems, The University of Melbourne, Parkville, Australia

    Wei Shi

  4. Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria

    Martina Minnich & Meinrad Busslinger

  5. School of BioSciences, The University of Melbourne, Parkville, Australia

    Simon Crawford

  6. Department of Mathematics and Statistics, The University of Melbourne, Parkville, Australia

    Gordon K Smyth

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Contributions

J.T. performed most experiments; W.S., Y.L. and G.K.S. performed the bioinformatics and statistical analyses; M.M. and M.B. provided data for chromatin immunoprecipitation followed by deep sequencing; S.C. performed electron microscopy; A.K. provided mouse models; S.L.N. supervised the study; and J.T. and S.L.N. wrote the manuscript, for which all authors provided editorial input.

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Integrated supplementary information

Supplementary Figure 1 Kinetics of PC survival in the absence of IRF4 or Blimp-1.

(a-e) In vivo gene ablation. (a-b) Schematic representation of the experimental plan. Cell transfer (a, c) and intact mice (b, d) as in Fig. 1a, b. (c) Left panel, frequency of Irf4fl/+CreERT2 or Irf4fl/-CreERT2 GFP+ spleen PCs (out of total spleen cells) was determined at the indicated day after mice were treated with tamoxifen treatment to induce Irf4 inactivation (reported by GFP expression). PCs were identified as CD138+B220lo. Right panel, frequency of Prdm1+/gfpCreERT2 (+/gfp) or Prdm1fl/gfpCreERT2 (fl/gfp) spleen PCs at the indicated day after tamoxifen treatment. PCs were identified as CD138+Blimp1-GFP+. (d) Frequency of spleen PCs from Prdm1+/gfpCreERT2 or Prdm1fl/gfpCreERT2 mice at the indicated day after tamoxifen treatment. Symbols represent data from a single mouse. Mean value is shown by a horizontal line. (e) Prdm1+/gfpCreERT2 or Prdm1fl/gfpCreERT2 mice were immunized with NP-KLH precipitated in alum and then treated with tamoxifen to induce Prdm1 inactivation 28 days later. PCs were identified as CD138+Blimp1-GFP+. Graphs show the proportion of PCs in spleen (left) and BM (right) at different time points after tamoxifen treatment. Each symbol represents an individual recipient mouse. Horizontal line is the mean. (f) In vitro gene inactivation. B cells were isolated from Prdm1+/gfpCreERT2 or Prdm1fl/gfpCreERT2 spleens and cultured with CD40L, IL-4 and IL-5 for 5 days. Cells were treated with 4-hydroxytamoxifen (100nM) at the indicated time points to induce Prdm1 inactivation. Cytometry profiles at day 5 of a representative experiment of 4 experiments. Boxes indicate the proportion of CD138+B220low PBs. P values compare the indicated groups using a paired t-test. * P<0.05, ** P<0.005.

Supplementary Figure 2 Efficient inactivation of Prdm1 and Xbp1 after tamoxifen treatment.

(a) Rag1−/− mice injected with isolated Prdm1+/gfpCreERT2 (+/gfp) or Prdm1fl/gfpCreERT2 (fl/gfp) B cells were treated with tamoxifen 2 days after transfer to induce Prdm1 inactivation. Splenic B cells (CD19+CD22+) and PCs (CD138+Blimp1-GFP+) 7 days after tamoxifen treatment are shown for a representative of 2 experiments. Each symbol represents a single recipient mouse. Horizontal line shows the mean. (b) PCR analysis showing the loss of the Prdm1 floxed allele (fl, 765 bp) in BM B cells (CD19+CD22+) and PCs (CD138+Blimp1-GFP+) from intact mice of the indicated genotypes, 21 days after tamoxifen treatment (as in Supplementary Fig. 1b). The location of the wild type (+, 611bp) and deleted alleles (-, 645bp) are indicated. Tail DNA from an untreated mouse was used as a control. (c) Abundance of junction read spanning exons 5-6 or exons 4-6, in Prdm1+/gfpCreERT2 or Prdm1fl/gfpCreERT2 PC RNAseq data. Shown is the number of junction reads per million mapped reads (RPM), excluding Ig sequences. Junction reads were identified using the Subjunc aligner. Data are the mean of two samples for each genotype. Comparison of exon 5-6 reads from Prdm1+/gfpCreERT2 or Prdm1fl/gfpCreERT2 indicates that the efficiency of deletion of the Prdm1 exon 5 was 87%. Reads spanning exons 4-6 only occur after exon 5 excision and are shown as a specificity control. (d) RNA sequencing tracks for Xbp1 in Xbp1+/+Prdm1+/gfpCreERT2 and Xbp1fl/flPrdm1+/gfpCreERT2 PCs 21 days after mice were treated with tamoxifen. The tamoxifen treatment has induced the complete deletion of Xbp1 exon 2. Data is representative of 2 experiments.

Supplementary Figure 3 Points at which Blimp-1 regulates the processing of Igh mRNA, the UPR and the mTOR pathway.

(a) Blimp-1 promotes the expression of the secreted form of Igh. In PCs two isoforms exist for each Ig isotype. Using Ighm as an example the minority membrane-bound isoform includes, in addition to the first four exons, two membrane specific exons encoding the transmembrane domain. The truncated secreted form uses an earlier polyadenylation signal sequence and is comprised of the first four exons and a specific secreted sequence upstream of the new polyadenylation site. Ell2, a direct activated target of Blimp-1, favors the processing of the secreted form of the Igh mRNA in PCs. (b) Blimp-1 regulation at the apex of the unfolded protein response (UPR). The UPR is composed of three arms; each one triggered through a transmembrane sensor (Ire1, Perk, Atf6) leads to the activation of a specific transcription factor (Xbp1s, Atf4, cleaved Atf6). Blimp-1 directly induces Atf6 and Ern1/Ire1 expression. Blimp-1 loss also significantly impacts Atf4 transcripts, through an indirect mechanism. As a result, Blimp-1 promotes the activity of all three arms of the UPR. (c) Blimp-1 promotes mTOR activity through the control of the upstream regulators of the pathway. Blimp-1 activates several crucial amino acid carriers (CD98, Asct2, PAT1) and the transferrin receptor (CD71) that activate mTORC1 kinase activity. In parallel, Blimp-1 represses transcription of Sestrin-1 and -3 (Sesn), preventing the inhibitory action of AMPK. Solid orange lines indicate direct regulation (as evidenced by Blimp-1 binding in the respective loci) and dashed lines denote indirect regulation.

Supplementary Figure 4 Blimp-1 and Xbp1 regulate distinct sets of target genes.

Whole genome RNA-sequencing analysis on BM PCs, analyzed as described in Fig. 2 and 6. (a) Graph shows the log2-Fold change (FC) of expression of the unfolded protein response (UPR) genes (as listed in Supplementary Table 3) for BM PCs from Prdm1fl/gfpCreERT2 versus Prdm1+/gfpCreERT2 and Xbp1fl/flPrdm1+/gfpCreERT2 versus Xbp1+/+Prdm1+/gfpCreERT2 mice. Genes are categorized depending the process their encoded protein is involved in. The mean FC for each genotype and category is shown by a horizontal line. (b) Venn diagram showing overlap and differences between Blimp-1 and Xbp1 target genes (FDR <0.05, normalized average expression ≥4 RPKM in at least one sample). (c) Heat map shows the expression of the signature genes of wild type follicular B cells (FoB)5 and BM PCs5 from Xbp1+/+Prdm1+/gfpCreERT2 (+/+) and Xbp1fl/flPrdm1+/gfpCreERT2 (fl/fl) mice. Data derive from 2 experiments.

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Tellier, J., Shi, W., Minnich, M. et al. Blimp-1 controls plasma cell function through the regulation of immunoglobulin secretion and the unfolded protein response. Nat Immunol 17, 323–330 (2016). https://doi.org/10.1038/ni.3348

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