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Bcl10-controlled Malt1 paracaspase activity is key for the immune suppressive function of regulatory T cells.

Marc Rosenbaum | Andreas Gewies | Konstanze Pechloff | Christoph Heuser | Thomas Engleitner | Torben Gehring | Lara Hartjes | Sabrina Krebs | Daniel Krappmann | Mark Kriegsmann | Wilko Weichert | Roland Rad | Christian Kurts | Jürgen Ruland
Nature communications | 2019

Regulatory T cells (Tregs) have crucial functions in the inhibition of immune responses. Their development and suppressive functions are controlled by the T cell receptor (TCR), but the TCR signaling mechanisms that mediate these effects remain ill-defined. Here we show that CARD11-BCL10-MALT1 (CBM) signaling mediates TCR-induced NF-κB activation in Tregs and controls the conversion of resting Tregs to effector Tregs under homeostatic conditions. However, in inflammatory milieus, cytokines can bypass the CBM requirement for this differentiation step. By contrast, CBM signaling, in a MALT1 protease-dependent manner, is essential for mediating the suppressive function of Tregs. In malignant melanoma models, acute genetic blockade of BCL10 signaling selectively in Tregs or pharmacological MALT1 inhibition enhances anti-tumor immune responses. Together, our data uncover a segregation of Treg differentiation and suppressive function at the CBM complex level, and provide a rationale to explore MALT1 inhibitors for cancer immunotherapy.

Pubmed ID: 31138793

Associated grants

  • Agency: EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council), International
    Id: 322865
  • Agency: Deutsche Forschungsgemeinschaft (German Research Foundation), International
    Id: SFB 1054/A04, B01
  • Agency: Deutsche Forschungsgemeinschaft (German Research Foundation), International
    Id: SFB 1335/P01, P07, P08
  • Agency: Deutsche Forschungsgemeinschaft (German Research Foundation), International
    Id: TRR 237/A10, B15
  • Agency: Deutsche Forschungsgemeinschaft (German Research Foundation), International
    Id: SFB 1371/P05
  • Agency: Deutsche Forschungsgemeinschaft (German Research Foundation), International
    Id: RU 695/9-1

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This is a list of tools and resources that we have found mentioned in this publication.


ATCC (tool)

RRID:SCR_001672

Global nonprofit biological resource center (BRC) and research organization that provides biological products, technical services and educational programs to private industry, government and academic organizations. Its mission is to acquire, authenticate, preserve, develop and distribute biological materials, information, technology, intellectual property and standards for the advancement and application of scientific knowledge. The primary purpose of ATCC is to use its resources and experience as a BRC to become the world leader in standard biological reference materials management, intellectual property resource management and translational research as applied to biomaterial development, standardization and certification. ATCC characterizes cell lines, bacteria, viruses, fungi and protozoa, as well as develops and evaluates assays and techniques for validating research resources and preserving and distributing biological materials to the public and private sector research communities.

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Ensembl (tool)

RRID:SCR_002344

Collection of genome databases for vertebrates and other eukaryotic species with DNA and protein sequence search capabilities. Used to automatically annotate genome, integrate this annotation with other available biological data and make data publicly available via web. Ensembl tools include BLAST, BLAT, BioMart and the Variant Effect Predictor (VEP) for all supported species.

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AxioVision Imaging System (tool)

RRID:SCR_002677

Digital image processing system where microscope settings and processing steps may be adjusted in single user interface. Can acquire images from variety of cameras. Includes software package for capturing, archiving and preparing images for publication. Allows users to visualize and present images in several dimensions. Functionality of imaging toolbox expands constantly with wide range of different modules that are tailored to specific applications or microscope accessories. This resource is duplicated by SCR_018376

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RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

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RRID:SCR_006802

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RRID:SCR_008452

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RRID:SCR_008520

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RRID:SCR_008983

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Sigma-Aldrich (tool)

RRID:SCR_008988

American chemical, life science and biotechnology company owned by Merck KGaA. Merger of Sigma Chemical Company and Aldrich Chemical Company. Provides organic and inorganic chemicals, building blocks, reagents, advanced materials and stable isotopes for chemical synthesis, medicinal chemistry and materials science, antibiotics, buffers, carbohydrates, enzymes, forensic tools, hematology and histology, nucleotides, proteins, peptides, amino acids and their derivatives.

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BD Biosciences (tool)

RRID:SCR_013311

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RRID:SCR_014551

Software suite for image acquisition and analysis. The software can be paired with high-quality cameras to maximize output quality and export it for sharing and research applications.

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DESeq2 (tool)

RRID:SCR_015687

Software package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.

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C57BL/6J (tool)

RRID:IMSR_JAX:000664

Mus musculus with name C57BL/6J from IMSR.

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RRID:CVCL_0158

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C57BL/6N (tool)

RRID:MGI:2159965

laboratory mouse with name C57BL/6N from MGI.

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