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Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation.
Bornancin, Frédéric; Renner, Florian; Touil, Ratiba; Sic, Heiko; Kolb, Yeter; Touil-Allaoui, Ismahane; Rush, James S; Smith, Paul A; Bigaud, Marc; Junker-Walker, Ursula; Burkhart, Christoph; Dawson, Janet; Niwa, Satoru; Katopodis, Andreas; Nuesslein-Hildesheim, Barbara; Weckbecker, Gisbert; Zenke, Gerhard; Kinzel, Bernd; Traggiai, Elisabetta; Brenner, Dirk; Brüstle, Anne; St Paul, Michael; Zamurovic, Natasa; McCoy, Kathy D; Rolink, Antonius; Régnier, Catherine H; Mak, Tak W; Ohashi, Pamela S; Patel, Dhavalkumar D; Calzascia, Thomas.
Afiliación
  • Bornancin F; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Renner F; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Touil R; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Sic H; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Kolb Y; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Touil-Allaoui I; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Rush JS; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Smith PA; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Bigaud M; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Junker-Walker U; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Burkhart C; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Dawson J; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Niwa S; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Katopodis A; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Nuesslein-Hildesheim B; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Weckbecker G; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Zenke G; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Kinzel B; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Traggiai E; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Brenner D; 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;
  • Brüstle A; 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;
  • St Paul M; Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C1, Canada;
  • Zamurovic N; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • McCoy KD; Maurice Müller Laboratories, University Clinic for Visceral Surgery and Medicine, University of Bern, 3010 Bern, Switzerland; and.
  • Rolink A; Developmental and Molecular Immunology, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
  • Régnier CH; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Mak TW; Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C1, Canada;
  • Ohashi PS; Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C1, Canada;
  • Patel DD; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland;
  • Calzascia T; Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland; thomas.calzascia@novartis.com.
J Immunol ; 194(8): 3723-34, 2015 Apr 15.
Article en En | MEDLINE | ID: mdl-25762782
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diferenciación Celular / Linfocitos T Reguladores / Caspasas / Proliferación Celular / Encefalomielitis Autoinmune Experimental / Linfocitos B Reguladores / Proteínas de Neoplasias Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Immunol Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diferenciación Celular / Linfocitos T Reguladores / Caspasas / Proliferación Celular / Encefalomielitis Autoinmune Experimental / Linfocitos B Reguladores / Proteínas de Neoplasias Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Immunol Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos