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- Publisher Website: 10.4049/jimmunol.1402254
- Scopus: eid_2-s2.0-84927603501
- PMID: 25762782
- WOS: WOS:000353247000021
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Article: Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation
Title | Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation |
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Authors | Bornancin, FrédéricRenner, FlorianTouil, RatibaSic, HeikoKolb, YeterTouil-Allaoui, IsmahaneRush, James S.Smith, Paul A.Bigaud, MarcJunker-Walker, UrsulaBurkhart, ChristophDawson, JanetNiwa, SatoruKatopodis, AndreasNuesslein-Hildesheim, BarbaraWeckbecker, GisbertZenke, GerhardKinzel, BerndTraggiai, ElisabettaBrenner, DirkBrüstle, AnnePaul, Michael StZamurovic, NatasaMcCoy, Kathy D.Rolink, AntoniusRégnier, Catherine H.Mak, Tak W.Ohashi, Pamela S.Patel, Dhavalkumar D.Calzascia, Thomas |
Issue Date | 2015 |
Citation | Journal of Immunology, 2015, v. 194, n. 8, p. 3723-3734 How to Cite? |
Abstract | Copyright © 2015 by The American Association of Immunologists, Inc. 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. |
Persistent Identifier | http://hdl.handle.net/10722/292876 |
ISSN | 2021 Impact Factor: 5.426 2020 SCImago Journal Rankings: 2.737 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Bornancin, Frédéric | - |
dc.contributor.author | Renner, Florian | - |
dc.contributor.author | Touil, Ratiba | - |
dc.contributor.author | Sic, Heiko | - |
dc.contributor.author | Kolb, Yeter | - |
dc.contributor.author | Touil-Allaoui, Ismahane | - |
dc.contributor.author | Rush, James S. | - |
dc.contributor.author | Smith, Paul A. | - |
dc.contributor.author | Bigaud, Marc | - |
dc.contributor.author | Junker-Walker, Ursula | - |
dc.contributor.author | Burkhart, Christoph | - |
dc.contributor.author | Dawson, Janet | - |
dc.contributor.author | Niwa, Satoru | - |
dc.contributor.author | Katopodis, Andreas | - |
dc.contributor.author | Nuesslein-Hildesheim, Barbara | - |
dc.contributor.author | Weckbecker, Gisbert | - |
dc.contributor.author | Zenke, Gerhard | - |
dc.contributor.author | Kinzel, Bernd | - |
dc.contributor.author | Traggiai, Elisabetta | - |
dc.contributor.author | Brenner, Dirk | - |
dc.contributor.author | Brüstle, Anne | - |
dc.contributor.author | Paul, Michael St | - |
dc.contributor.author | Zamurovic, Natasa | - |
dc.contributor.author | McCoy, Kathy D. | - |
dc.contributor.author | Rolink, Antonius | - |
dc.contributor.author | Régnier, Catherine H. | - |
dc.contributor.author | Mak, Tak W. | - |
dc.contributor.author | Ohashi, Pamela S. | - |
dc.contributor.author | Patel, Dhavalkumar D. | - |
dc.contributor.author | Calzascia, Thomas | - |
dc.date.accessioned | 2020-11-17T14:57:24Z | - |
dc.date.available | 2020-11-17T14:57:24Z | - |
dc.date.issued | 2015 | - |
dc.identifier.citation | Journal of Immunology, 2015, v. 194, n. 8, p. 3723-3734 | - |
dc.identifier.issn | 0022-1767 | - |
dc.identifier.uri | http://hdl.handle.net/10722/292876 | - |
dc.description.abstract | Copyright © 2015 by The American Association of Immunologists, Inc. 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<sup>PD/PD</sup>) and compared their phenotype with that of MALT1 knockout animals (Malt1<sup>-/-</sup>). Malt1<sup>PD/PD</sup> 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<sup>-/-</sup> 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, Malt1<sup>PD/PD</sup> mice were protected in a Th17-dependent experimental autoimmune encephalomyelitis model. Surprisingly, Malt1<sup>PD/PD</sup> 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<sup>PD/PD</sup> 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. | - |
dc.language | eng | - |
dc.relation.ispartof | Journal of Immunology | - |
dc.title | Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation | - |
dc.type | Article | - |
dc.description.nature | link_to_OA_fulltext | - |
dc.identifier.doi | 10.4049/jimmunol.1402254 | - |
dc.identifier.pmid | 25762782 | - |
dc.identifier.scopus | eid_2-s2.0-84927603501 | - |
dc.identifier.volume | 194 | - |
dc.identifier.issue | 8 | - |
dc.identifier.spage | 3723 | - |
dc.identifier.epage | 3734 | - |
dc.identifier.eissn | 1550-6606 | - |
dc.identifier.isi | WOS:000353247000021 | - |
dc.identifier.f1000 | 725387389 | - |
dc.identifier.issnl | 0022-1767 | - |