Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation

Frédéric Bornancin, Florian Renner, Ratiba Touil, Heiko Sic, Yeter Kolb, Ismahane Touil-Allaoui, James S. Rush, Paul A. Smith, Marc Bigaud, Ursula Junker-Walker, Christoph Burkhart, Janet Dawson, Satoru Niwa, Andreas Katopodis, Barbara Nuesslein-Hildesheim, Gisbert Weckbecker, Gerhard Zenke, Bernd Kinzel, Elisabetta Traggiai, Dirk BrennerAnne Brüstle, Michael St Paul, Natasa Zamurovic, Kathy D. McCoy, Antonius Rolink, Catherine H. Régnier, Tak W. Mak, Pamela S. Ohashi, Dhavalkumar D. Patel, Thomas Calzascia*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

91 Citations (Scopus)

Abstract

The paracaspase MALT1 plays an important role in immune receptor-driven signaling pathways leading to NF-κB activation. MALT1 promotes signaling by acting as a scaffold, recruiting downstream signaling proteins, as well as by proteolytic cleavage of multiple substrates. However, the relative contributions of these two different activities to T and B cell function are not well understood. To investigate how MALT1 proteolytic activity contributes to overall immune cell regulation, we generated MALT1 protease-deficient mice (Malt1PD/PD) and compared their phenotype with that of MALT1 knockout animals (Malt1-/-). Malt1PD/PD mice displayed defects in multiple cell types including marginal zone B cells, B1 B cells, IL-10-producing B cells, regulatory T cells, and mature T and B cells. In general, immune defects were more pronounced in Malt1-/- animals. Both mouse lines showed abrogated B cell responses upon immunization with T-dependent and T-independent Ags. In vitro, inactivation of MALT1 protease activity caused reduced stimulation-induced T cell proliferation, impaired IL-2 and TNF-a production, as well as defective Th17 differentiation. Consequently, Malt1PD/PD mice were protected in a Th17-dependent experimental autoimmune encephalomyelitis model. Surprisingly, Malt1PD/PD animals developed a multiorgan inflammatory pathology, characterized by Th1 and Th2/0 responses and enhanced IgG1 and IgE levels, which was delayed by wild-type regulatory T cell reconstitution. We therefore propose that the pathology characterizing Malt1PD/PD animals arises from an immune imbalance featuring pathogenic Th1- and Th2/0-skewed effector responses and reduced immunosuppressive compartments. These data uncover a previously unappreciated key function of MALT1 protease activity in immune homeostasis and underline its relevance in human health and disease.

Original languageEnglish
Pages (from-to)3723-3734
Number of pages12
JournalJournal of Immunology
Volume194
Issue number8
DOIs
Publication statusPublished - 15 Apr 2015

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