Details

Autor(en) / Beteiligte

• 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

Titel

Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation

Ist Teil von

• The Journal of immunology (1950), 2015-04, Vol.194 (8), p.3723-3734

Ort / Verlag

United States

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.