Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation
Data(s) |
15/04/2015
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Resumo |
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. |
Formato |
application/pdf |
Identificador |
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; ... (2015). Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation. Journal of immunology, 194(8), pp. 3723-3734. American Association of Immunologists 10.4049/jimmunol.1402254 <http://dx.doi.org/10.4049/jimmunol.1402254> doi:10.7892/boris.77487 info:doi:10.4049/jimmunol.1402254 info:pmid:25762782 urn:issn:0022-1767 |
Idioma(s) |
eng |
Publicador |
American Association of Immunologists |
Relação |
http://boris.unibe.ch/77487/ |
Direitos |
info:eu-repo/semantics/restrictedAccess |
Fonte |
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; ... (2015). Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation. Journal of immunology, 194(8), pp. 3723-3734. American Association of Immunologists 10.4049/jimmunol.1402254 <http://dx.doi.org/10.4049/jimmunol.1402254> |
Palavras-Chave | #610 Medicine & health |
Tipo |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion PeerReviewed |