Effector functions of inflammatory IL-17–producing Th (Th17) cells have been linked to autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). However, what determines Th17 cell encephalitogenicity is still unresolved. Here, we show that after EAE induction, mice deficient for the NF-κB regulator MALT1 (Malt1–/– mice) exhibit strong lymphocytic infiltration in the CNS, but do not develop any clinical signs of EAE. Loss of Malt1 interfered with expression of the Th17 effector cytokines IL-17 and GM-CSF both in vitro and in vivo. In line with their impaired GM-CSF secretion, Malt1–/– Th cells failed to recruit myeloid cells to the CNS to sustain neuroinflammation, whereas autoreactive WT Th cells successfully induced EAE in Malt1–/– hosts. In contrast, Malt1 deficiency did not affect Th1 cells. Despite their significantly decreased secretion of Th17 effector cytokines, Malt1–/– Th17 cells showed normal expression of lineage-specific transcription factors. Malt1–/– Th cells failed to cleave RelB, a suppressor of canonical NF-κB, and exhibited altered cellular localization of this protein. Our results indicate that MALT1 is a central, cell-intrinsic factor that determines the encephalitogenic potential of inflammatory Th17 cells in vivo.
Anne Brüstle, Dirk Brenner, Christiane B. Knobbe, Philipp A. Lang, Carl Virtanen, Brian M. Hershenfield, Colin Reardon, Sonja M. Lacher, Jürgen Ruland, Pamela S. Ohashi, Tak W. Mak
Title and authors | Publication | Year |
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Specific covalent inhibition of MALT1 paracaspase suppresses B-cell lymphoma growth
Lorena Fontán, Qi Qiao, John M. Hatcher, Gabriella Casalena, Ilkay Us, Matt Teater, Matthew Durant, Guangyan Du, Min Xia, Natalia Bilchuk, Spandan Chennamadhavuni, Giuseppe Palladino, Giorgio Inghirami, Ulrike Philippar, Hao Wu, David A. Scott, Nathanael S. Gray, Ari Melnick |
Journal of Clinical Investigation | 2018 |
The CBM-opathies—A Rapidly Expanding Spectrum of Human Inborn Errors of Immunity Caused by Mutations in the CARD11-BCL10-MALT1 Complex
HY Lu, BM Bauman, S Arjunaraja, B Dorjbal, JD Milner, AL Snow, SE Turvey |
Frontiers in immunology | 2018 |
Holding All the CARDs: How MALT1 Controls CARMA/CARD-Dependent Signaling
M Juilland, M Thome |
Frontiers in immunology | 2018 |
MALT1 Controls Attenuated Rabies Virus by Inducing Early Inflammation and T Cell Activation in the Brain
E Kip, J Staal, L Verstrepen, HG Tima, S Terryn, M Romano, K Lemeire, V Suin, A Hamouda, M Kalai, R Beyaert, SV Gucht, RE Dutch |
Journal of virology | 2018 |
Inhibition of MALT1 Decreases Neuroinflammation and Pathogenicity of Virulent Rabies Virus in Mice
E Kip, J Staal, HG Tima, L Verstrepen, M Romano, K Lemeire, V Suin, A Hamouda, M Baens, C Libert, M Kalai, SV Gucht, R Beyaert, RE Dutch |
Journal of virology | 2018 |
Psoriasis: A STAT3-Centric View.
Calautti E, Avalle L, Poli V |
International journal of molecular sciences | 2018 |