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Transcriptional control of plasma cell development and function

Transcriptional control of plasma cell development and function

Objective

Antibody-secreting cells consisting of short-lived proliferating plasmablasts and long-lived quiescent plasma cells are essential for the acute response to infection and long-term protection of the host against pathogens. Only a few regulators (Blimp1, IRF4, XBP1, Aiolos, Ikaros and E-proteins) have been implicated in the transcriptional control of antibody-secreting cells, and their target genes, with the exception of Blimp1 and E-proteins, are still unknown. This proposal aims to systematically identify key players in the development and function of antibody-secreting cells by using the CRISPR/Cas9 and Cre/loxP methods.
For this, we improved existing protocols to extend the duration of in vitro plasmablast differentiation and showed that Rosa26(Cas9/+) B cells infected with Blimp1 or Xbp1 sgRNA-expressing retroviruses recapitulated the Blimp1 and Xbp1 mutant phenotypes in this proof-of-principle experiment. Moreover, Cre retrovirus-mediated deletion of Irf4, Ikaros and Aiolos strongly impaired plasmablast differentiation in this optimized system.
To discover new regulators of plasma cell differentiation, CRISPR/Cas9-based screens will be performed with pooled sgRNA libraries targeting all known upregulated genes in plasmablasts and plasma cells, followed by individual validation of the best hits. Selected top-ranked genes will be analyzed in vivo by conditional mutagenesis with newly generated, plasma cell-specific Cre lines. Regulated target genes of IRF4, Ikaros, Aiolos, XBP1 and the XBP1-regulated transcription factor Bhlha15 will be identified in plasmablasts by ChIP- and RNA-seq analyses. Target genes with potentially interesting functions will be further characterized by CRISPR/Cas9- or Cre/loxP-mediated mutagenesis.
These experiments will provide fundamentally new insight into the molecular mechanisms controlling the development and function of antibody-secreting cells, which are the essential effector cells of humoral immunity.
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Host institution

FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH

Address

Campus-Vienna-Biocenter 1
1030 Wien

Austria

Activity type

Private for-profit entities (excluding Higher or Secondary Education Establishments)

EU Contribution

€ 2 500 000

Beneficiaries (1)

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FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH

Austria

EU Contribution

€ 2 500 000

Project information

Grant agreement ID: 740349

Status

Ongoing project

  • Start date

    1 January 2018

  • End date

    31 December 2022

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 2 500 000

  • EU contribution

    € 2 500 000

Hosted by:

FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH

Austria