title: Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity.
abstract: The protease activity of the paracaspase Malt1 has recently gained interest as a drug target for immunomodulation and the treatment of diffuse large B-cell lymphomas. To address the consequences of Malt1 protease inactivation on the immune response in vivo, we generated knock-in mice expressing a catalytically inactive C472A mutant of Malt1 that conserves its scaffold function. Like Malt1-deficient mice, knock-in mice had strong defects in the activation of lymphocytes, NK and dendritic cells, and the development of B1 and marginal zone B cells and were completely protected against the induction of autoimmune encephalomyelitis. Malt1 inactivation also protected the mice from experimental induction of colitis. However, Malt1 knock-in mice but not Malt1-deficient mice spontaneously developed signs of autoimmune gastritis that correlated with an absence of Treg cells, an accumulation of T cells with an activated phenotype and high serum levels of IgE and IgG1. Thus, removal of the enzymatic activity of Malt1 efficiently dampens the immune response, but favors autoimmunity through impaired Treg development, which could be relevant for therapeutic Malt1-targeting strategies.
authors.affiliation: Department of Biochemistry, Center of Immunity and Infection, University of Lausanne, Epalinges, Switzerland.
authors.forename: Maike
authors.initials: M
authors.lastname: Jaworski
authors.affiliation: Centre Hospitalier Universitaire Vaudois, Service de Pneumologie, Lausanne, Switzerland.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Marsland
authors.affiliation: Department of Oncology, Ludwig Center for Cancer Research, University of Lausanne, Epalinges, Switzerland.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Gehrig
authors.affiliation: Department of Oncology, Ludwig Center for Cancer Research, University of Lausanne, Epalinges, Switzerland.
authors.forename: Werner
authors.initials: W
authors.lastname: Held
authors.affiliation: Department of Biochemistry, Center of Immunity and Infection, University of Lausanne, Epalinges, Switzerland.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Favre
authors.affiliation: Department of Biochemistry, Center of Immunity and Infection, University of Lausanne, Epalinges, Switzerland.
authors.forename: Sanjiv A
authors.initials: SA
authors.lastname: Luther
authors.affiliation: Department of Biochemistry, Center of Immunity and Infection, University of Lausanne, Epalinges, Switzerland.
authors.forename: Mai
authors.initials: M
authors.lastname: Perroud
authors.affiliation: Centre Hospitalier Universitaire Vaudois, Transplantation Centre, Lausanne, Switzerland.
authors.forename: Déla
authors.initials: D
authors.lastname: Golshayan
authors.affiliation: Centre Hospitalier Universitaire Vaudois, Service de Dermatologie et Vénéréologie, Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Gaide
authors.affiliation: Department of Biochemistry, Center of Immunity and Infection, University of Lausanne, Epalinges, Switzerland margot.thomemiazza@unil.ch.
authors.forename: Margot
authors.initials: M
authors.lastname: Thome
mesh_terms: D019264:Adoptive Transfer; D000704:Analysis of Variance; D000818:Animals; D015551:Autoimmunity / Q000235:genetics*; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D003092:Colitis / Q000276:immunology* / Q000473:pathology; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055879:Gene Knock-In Techniques; D020868:Gene Silencing; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D009363:Neoplasm Proteins; C499308:Rag2 protein, mouse; D007073:Immunoglobulin E; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
keywords: EAE; NF‐κB; colitis; gastritis; paracaspase