title: Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation.
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 (Malt1(PD/PD)) and compared their phenotype with that of MALT1 knockout animals (Malt1(-/-)). Malt1(PD/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-α production, as well as defective Th17 differentiation. Consequently, Malt1(PD/PD) mice were protected in a Th17-dependent experimental autoimmune encephalomyelitis model. Surprisingly, Malt1(PD/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 Malt1(PD/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.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bornancin
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Florian
authors.initials: F
authors.lastname: Renner
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Ratiba
authors.initials: R
authors.lastname: Touil
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Heiko
authors.initials: H
authors.lastname: Sic
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Yeter
authors.initials: Y
authors.lastname: Kolb
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Ismahane
authors.initials: I
authors.lastname: Touil-Allaoui
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: James S
authors.initials: JS
authors.lastname: Rush
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Paul A
authors.initials: PA
authors.lastname: Smith
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Marc
authors.initials: M
authors.lastname: Bigaud
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Ursula
authors.initials: U
authors.lastname: Junker-Walker
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Christoph
authors.initials: C
authors.lastname: Burkhart
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Janet
authors.initials: J
authors.lastname: Dawson
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Satoru
authors.initials: S
authors.lastname: Niwa
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Andreas
authors.initials: A
authors.lastname: Katopodis
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Barbara
authors.initials: B
authors.lastname: Nuesslein-Hildesheim
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Gisbert
authors.initials: G
authors.lastname: Weckbecker
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Gerhard
authors.initials: G
authors.lastname: Zenke
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Bernd
authors.initials: B
authors.lastname: Kinzel
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Traggiai
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C1, Canada; Department of Infection and Immunity, Luxembourg Institute of Health, L-4354 Esch-Sur-Alzette, Luxembourg;
authors.forename: Dirk
authors.initials: D
authors.lastname: Brenner
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C1, Canada; Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra ACT 2601, Australia;
authors.forename: Anne
authors.initials: A
authors.lastname: Brüstle
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C1, Canada;
authors.forename: Michael
authors.initials: M
authors.lastname: St Paul
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Natasa
authors.initials: N
authors.lastname: Zamurovic
authors.affiliation: Maurice Müller Laboratories, University Clinic for Visceral Surgery and Medicine, University of Bern, 3010 Bern, Switzerland; and.
authors.forename: Kathy D
authors.initials: KD
authors.lastname: McCoy
authors.affiliation: Developmental and Molecular Immunology, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Antonius
authors.initials: A
authors.lastname: Rolink
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Régnier
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C1, Canada;
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C1, Canada;
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
authors.forename: Dhavalkumar D
authors.initials: DD
authors.lastname: Patel
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland; thomas.calzascia@novartis.com.
authors.forename: Thomas
authors.initials: T
authors.lastname: Calzascia
mesh_terms: D000818:Animals; D060151:B-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D020169:Caspases / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007073:Immunoglobulin E / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology
chemical_list: C556062:IL10 protein, mouse; D007074:Immunoglobulin G; D007376:Interleukin-2; D009363:Neoplasm Proteins; D016753:Interleukin-10; D007073:Immunoglobulin E; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein