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

April 15, 2015 By:
  • Bornancin F
  • Renner F
  • Touil R
  • Sic H
  • Kolb Y
  • Touil-Allaoui I
  • Rush JS
  • Smith PA
  • Bigaud M
  • Junker-Walker U
  • Burkhart C
  • Dawson J
  • Niwa S
  • Katopodis A
  • Nuesslein-Hildesheim B
  • Weckbecker G
  • Zenke G
  • Kinzel B
  • Traggiai E
  • Brenner D
  • Brustle A
  • St Paul M
  • Zamurovic N
  • McCoy KD
  • Rolink A
  • Regnier CH
  • Mak TW
  • Ohashi PS
  • Patel DD
  • Calzascia T.

The paracaspase MALT1 plays an important role in immune receptor-driven signaling pathways leading to NF-kappaB 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-alpha 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.

2015 Apr. J Immunol.194(8):3723-34. Epub 2015 Mar 11.
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