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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Li X, Lin L, Duan X, Dai J, Hu T, Cai H |
Immunity, Inflammation and Disease | 2024 |
PIM kinases regulate early human Th17 cell differentiation.
Buchacher T, Shetty A, Koskela SA, Smolander J, Kaukonen R, Sousa AGG, Junttila S, Laiho A, Rundquist O, Lönnberg T, Marson A, Rasool O, Elo LL, Lahesmaa R |
Cell Reports | 2023 |
Clonotypic analysis of protective influenza M2e-specific lung resident Th17 memory cells reveals extensive functional diversity
A Omokanye, L Ong, C Lebrero-Fernandez, V Bernasconi, K Schön, A Strömberg, M Bemark, X Saelens, P Czarnewski, N Lycke |
Mucosal Immunology | 2022 |
NF-κB Signaling and Inflammation—Drug Repurposing to Treat Inflammatory Disorders?
A Roberti, L Chaffey, D Greaves |
Biology : open access journal | 2022 |
Aberrant blood MALT1 and its relevance with multiple organic dysfunctions, T helper cells, inflammation, and mortality risk of sepsis patients
Y Wang, Q Huang, F He |
Journal of Clinical Laboratory Analysis | 2022 |
A systematic comparison of FOSL1, FOSL2 and BATF-mediated transcriptional regulation during early human Th17 differentiation
A Shetty, S Tripathi, S Junttila, T Buchacher, R Biradar, S Bhosale, T Envall, A Laiho, R Moulder, O Rasool, S Galande, L Elo, R Lahesmaa |
Nucleic Acids Research | 2022 |
The Role of the CBM Complex in Allergic Inflammation and Disease
DeVore SB, Khurana Hershey GK |
Journal of Allergy and Clinical Immunology | 2022 |
Cholinergic control of Th17 cell pathogenicity in experimental autoimmune encephalomyelitis
Nechanitzky R, Nechanitzky D, Ramachandran P, Duncan GS, Zheng C, Göbl C, Gill KT, Haight J, Wakeham AC, Snow BE, Bradaschia-Correa V, Ganguly M, Lu Z, Saunders ME, Flavell RA, Mak TW |
Cell Death and Differentiation | 2022 |
NF-κB: At the Borders of Autoimmunity and Inflammation
L Barnabei, E Laplantine, W Mbongo, F Rieux-Laucat, R Weil |
Frontiers in immunology | 2021 |
MALT1 positively correlates with Th1 cells, Th17 cells, and their secreted cytokines and also relates to disease risk, severity, and prognosis of acute ischemic stroke
X Chen, X Zhang, L Lan, G Xu, Y Li, S Huang |
Journal of Clinical Laboratory Analysis | 2021 |
HuR Plays a Positive Role to Strengthen the Signaling Pathways of CD4+ T Cell Activation and Th17 Cell Differentiation
S Yu, M Tripod, U Atasoy, J Chen, Z Xu |
Journal of Immunology Research | 2021 |
NF‐κB signaling in inflammation and cancer
T Zhang, C Ma, Z Zhang, H Zhang, H Hu |
2021 | |
Blood MALT1, Th1, and Th17 cells are dysregulated, inter‐correlated, and correlated with disease activity in rheumatoid arthritis patients; meanwhile, MALT1 decline during therapy relates to treatment outcome
Z Ye, L Chen, Y Fang, L Zhao |
Journal of Clinical Laboratory Analysis | 2021 |
GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis
Xichun Xia, Guangchao Cao, Guodong Sun, Leqing Zhu, Yixia Tian, Yueqi Song, Chengbin Guo, Xiao Wang, Jingxiang Zhong, Wei Zhou, Peng Li, Hua Zhang, Jianlei Hao, Zhizhong Li, Liehua Deng, Zhinan Yin, Yunfei Gao |
Journal of Clinical Investigation | 2020 |
Therapeutic Potential of Targeting Malt1-Dependent TCR Downstream Signaling to Promote the Survival of MHC-Mismatched Allografts
L Govender, J Mikulic, JC Wyss, O Gaide, M Thome, D Golshayan |
Frontiers in immunology | 2020 |
A MALT1 inhibitor suppresses human myeloid DC, effector T-cell and B-cell responses and retains Th1/regulatory T-cell homeostasis
C Dumont, U Sivars, T Andreasson, L Odqvist, J Mattsson, A DeMicco, K Pardali, G Johansson, L Yrlid, RJ Cox, F Seeliger, M Larsson, U Gehrmann, AM Davis, O Vaarala, M Cebecauer |
PloS one | 2020 |
Biological characteristics of transcription factor RelB in different immune cell types: implications for the treatment of multiple sclerosis
M Yang, L Sun, J Han, C Zheng, H Liang, J Zhu, T Jin |
Molecular brain | 2019 |
MALT1 Proteolytic Activity Suppresses Autoimmunity in a T Cell Intrinsic Manner
A Demeyer, I Skordos, Y Driege, M Kreike, T Hochepied, M Baens, J Staal, R Beyaert |
Frontiers in immunology | 2019 |
RANTES-induced invasion of Th17 cells into substantia nigra potentiates dopaminergic cell loss in MPTP mouse model of Parkinson's disease
D Dutta, M Kundu, S Mondal, A Roy, S Ruehl, DA Hall, K Pahan |
Neurobiology of Disease | 2019 |
Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation
JJ Cho, Z Xu, U Parthasarathy, TT Drashansky, EY Helm, AN Zuniga, KJ Lorentsen, S Mansouri, JY Cho, MJ Edelmann, DM Duong, T Gehring, T Seeholzer, D Krappmann, MN Uddin, D Califano, RL Wang, L Jin, H Li, D Lv, D Zhou, L Zhou, D Avram |
Nature Communications | 2019 |
The role of E3 ubiquitin ligase HECTD3 in cancer and beyond
Q Jiang, F Li, Z Cheng, Y Kong, C Chen |
Cellular and Molecular Life Sciences | 2019 |
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 |
NF-κB signaling in inflammation
T Liu, L Zhang, D Joo, SC Sun |
Signal Transduction and Targeted Therapy | 2017 |
T cell responses in the central nervous system
T Korn, A Kallies |
Nature Reviews Immunology | 2017 |
Inhaled Pollutants: The Molecular Scene behind Respiratory and Systemic Diseases Associated with Ultrafine Particulate Matter
H Traboulsi, N Guerrina, M Iu, D Maysinger, P Ariya, C Baglole |
International journal of molecular sciences | 2017 |
Tumor Necrosis Factor-Mediated Survival of CD169 + Cells Promotes Immune Activation during Vesicular Stomatitis Virus Infection
PV Shinde, HC Xu, SK Maney, A Kloetgen, S Namineni, Y Zhuang, N Honke, N Shaabani, N Bellora, M Doerrenberg, M Trilling, VI Pozdeev, N van Rooijen, S Scheu, K Pfeffer, PR Crocker, M Tanaka, S Duggimpudi, P Knolle, M Heikenwalder, J Ruland, TW Mak, D Brenner, AA Pandyra, JI Hoell, A Borkhardt, D Häussinger, KS Lang, PA Lang, BR Williams |
Journal of virology | 2017 |
K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression
Z Hao, Y Sheng, GS Duncan, WY Li, C Dominguez, J Sylvester, YW Su, GH Lin, BE Snow, D Brenner, A You-Ten, J Haight, S Inoue, A Wakeham, A Elford, S Hamilton, Y Liang, JC Zúñiga-Pflücker, HH He, PS Ohashi, TW Mak |
Nature Communications | 2017 |
NF-κB Pathways in the Pathogenesis of Multiple Sclerosis and the Therapeutic Implications
SM Leibowitz, J Yan |
Frontiers in molecular neuroscience | 2016 |
IKKβ-mediated inflammatory myeloid cell activation exacerbates experimental autoimmune encephalomyelitis by potentiating Th1/Th17 cell activation and compromising blood brain barrier
MJ Lee, SJ Bing, J Choi, M Jang, G Lee, H Lee, BS Chang, Y Jee, SJ Lee, IH Cho |
Molecular Neurodegeneration | 2016 |
GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis
JP Hussman, AH Beecham, M Schmidt, ER Martin, JL McCauley, JM Vance, JL Haines, MA Pericak-Vance |
Genes and Immunity | 2016 |
Alternative splicing of MALT1 controls signalling and activation of CD4+ T cells
I Meininger, RA Griesbach, D Hu, T Gehring, T Seeholzer, A Bertossi, J Kranich, A Oeckinghaus, AC Eitelhuber, U Greczmiel, A Gewies, M Schmidt-Supprian, J Ruland, T Brocker, V Heissmeyer, F Heyd, D Krappmann |
Nature Communications | 2016 |
Trim32 Deficiency Enhances Th2 Immunity and Predisposes to Features of Atopic Dermatitis
Y Liu, Z Wang, RD la Torre, A Barling, T Tsujikawa, N Hornick, J Hanifin, E Simpson, Y Wang, E Swanzey, A Wortham, H Ding, LM Coussens, M Kulesz-Martin |
Journal of Investigative Dermatology | 2016 |
T cell-intrinsic function of Mir-21 in Th17 differentiation and autoimmunity
Murugaiyan Gopal, Andre Pires da Cunha, Amrendra Ajay, Nicolle Joller, Lucien Garo, Sowmiya Kumaradevan, Nir Yosef, Vishal Vaidya, Howard L. Weiner |
Journal of Clinical Investigation | 2015 |
Translational utility of experimental autoimmune encephalomyelitis: recent developments
M Jagodic, AO Guerreiro-Cacais, H Laaksonen, S Flytzani, M Ndiaye, T Olsson |
Journal of inflammation research | 2015 |
MALT1 is an intrinsic regulator of regulatory T cells
A Brüstle, D Brenner, CB Knobbe-Thomsen, M Cox, PA Lang, KS Lang, TW Mak |
Cell Death and Differentiation | 2015 |
Is DUBA putting the brake on Th17 cells?
A Brüstle |
Immunology and Cell Biology | 2015 |
Decreased expression of the NF-κB family member RelB in lung fibroblasts from Smokers with and without COPD potentiates cigarette smoke-induced COX-2 expression
JA Sheridan, M Zago, P Nair, PZ Li, J Bourbeau, WC Tan, Q Hamid, DH Eidelman, AL Benedetti, CJ Baglole |
Respiratory Research | 2015 |
MALT1 Protease Activity Is Required for Innate and Adaptive Immune Responses
JW Yu, S Hoffman, AM Beal, A Dykon, MA Ringenberg, AC Hughes, L Dare, AD Anderson, J Finger, V Kasparcova, D Rickard, SB Berger, J Ramanjulu, JG Emery, PJ Gough, J Bertin, KP Foley, A Krieg |
PloS one | 2015 |
Inhibition of System Xc- Transporter Attenuates Autoimmune Inflammatory Demyelination
KS Evonuk, BJ Baker, RE Doyle, CE Moseley, CM Sestero, BP Johnston, PD Sarno, A Tang, I Gembitsky, SJ Hewett, CT Weaver, C Raman, TM DeSilva |
Journal of immunology (Baltimore, Md. : 1950) | 2015 |
The role of the ubiquitin-editing enzyme A20 in diseases of the central nervous system and other pathological processes
A Abbasi, K Forsberg, F Bischof |
Frontiers in molecular neuroscience | 2015 |
The Paracaspase MALT1
J Hachmann, GS Salvesen |
Biochimie | 2015 |
The paracaspase MALT1: biological function and potential for therapeutic inhibition
M Jaworski, M Thome |
Cellular and Molecular Life Sciences | 2015 |
Inhibitor of NF B Kinase Subunit 2 Blockade Hinders the Initiation but Aggravates the Progression of Crescentic GN
J Gotot, E Piotrowski, MS Otte, AP Tittel, G Linlin, C Yao, K Ziegelbauer, U Panzer, N Garbi, C Kurts, F Thaiss |
Journal of the American Society of Nephrology : JASN | 2015 |
Alternative Expression Pattern of MALT1-A20-NF-κB in Patients with Rheumatoid Arthritis
X Wang, L Zhu, Z Liao, F Zhang, L Xu, Y Xu, S Chen, L Yang, Y Zhou, Y Li |
Journal of Immunology Research | 2014 |
Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation
CC Lin, TR Bradstreet, EA Schwarzkopf, J Sim, JA Carrero, C Chou, LE Cook, T Egawa, R Taneja, TL Murphy, JH Russell, BT Edelson |
Nature Communications | 2014 |
T-bet Is Critical for the Development of Acute Graft-versus-Host Disease through Controlling T Cell Differentiation and Function
J Fu, D Wang, Y Yu, J Heinrichs, Y Wu, S Schutt, K Kaosaard, C Liu, K Haarberg, D Bastian, DG McDonald, C Anasetti, XZ Yu |
Journal of immunology (Baltimore, Md. : 1950) | 2014 |
NF-κB Activation in T Helper 17 Cell Differentiation
SH Park, G Cho, SG Park |
Immune Network | 2014 |
Toso controls encephalitogenic immune responses by dendritic cells and regulatory T cells
D Brenner, A Brustle, GH Lin, PA Lang, GS Duncan, CB Knobbe-Thomsen, MS Paul, C Reardon, MW Tusche, B Snow, SR Hamilton, A Pfefferle, SO Gilani, PS Ohashi, KS Lang, TW Mak |
Proceedings of the National Academy of Sciences | 2014 |
Annotation of functional variation within non-MHC MS susceptibility loci through bioinformatics analysis
FB Briggs, LJ Leung, LF Barcellos |
Genes and Immunity | 2014 |
Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote TH17 differentiation
KM Jeltsch, D Hu, S Brenner, J Zöller, GA Heinz, D Nagel, KU Vogel, N Rehage, SC Warth, SL Edelmann, R Gloury, N Martin, C Lohs, M Lech, JE Stehklein, A Geerlof, E Kremmer, A Weber, HJ Anders, I Schmitz, M Schmidt-Supprian, M Fu, H Holtmann, D Krappmann, J Ruland, A Kallies, M Heikenwalder, V Heissmeyer |
Nature Immunology | 2014 |
MALT1 protease: equilibrating immunity versus tolerance
A Bertossi, D Krappmann |
The EMBO Journal | 2014 |
Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity
M Jaworski, BJ Marsland, J Gehrig, W Held, S Favre, SA Luther, M Perroud, D Golshayan, O Gaide, M Thome |
The EMBO Journal | 2014 |
A Homozygous mucosa-associated ly 1 mphoid tissue 1 (MALT1) mutation in a family with 2 combined immunodeficiency
HH Jabara, T Ohsumi, J Chou, MJ Massaad, H Benson, A Megarbane, E Chouery, R Mikhael, O Gorka, A Gewies, P Portales, T Nakayama, H Hosokawa, P Revy, H Herrod, FL Deist, G Lefranc, J Ruland, RS Geha |
Journal of Allergy and Clinical Immunology | 2013 |