Abstract
The paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) regulates nuclear-factor-kappa-B (NF-κB) activation downstream of surface receptors with immunoreceptor tyrosine-based activation motifs (ITAMs), such as the B-cell or T-cell receptor and has thus emerged as a therapeutic target for autoimmune diseases. However, recent reports demonstrate the development of lethal autoimmune inflammation due to the excessive production of interferon gamma (IFN-ɣ) and defective differentiation of regulatory T-cells in genetically modified mice deficient in MALT1 paracaspase activity. To address this issue, we explored the effects of pharmacological MALT1 inhibition on the balance between T-effector and regulatory T-cells. Here we demonstrate that allosteric inhibition of MALT1 suppressed Th1, Th17 and Th1/Th17 effector responses, and inhibited T-cell dependent B-cell proliferation and antibody production. Allosteric MALT1 inhibition did not interfere with the suppressive function of human T-regulatory cells, although it impaired de novo differentiation of regulatory T-cells from naïve T-cells. Treatment with an allosteric MALT1 inhibitor alleviated the cytokine storm, including IFN-ɣ, in a mouse model of acute T-cell activation, and long-term treatment did not lead to an increase in IFN-ɣ producing CD4 cells or tissue inflammation. Together, our data demonstrate that the effects of allosteric inhibition of MALT1 differ from those seen in mice with proteolytically inactive MALT1, and thus we believe that MALT1 is a viable target for B and T-cell driven autoimmune diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Allosteric Regulation / drug effects
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Animals
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B-Lymphocytes / drug effects*
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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Cells, Cultured
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Dendritic Cells / drug effects*
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Dendritic Cells / immunology
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Female
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Fluorescence Resonance Energy Transfer
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Healthy Volunteers
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Humans
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Injections, Intraperitoneal
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Lymphocyte Activation / drug effects
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Mice
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Mice, Knockout
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / antagonists & inhibitors*
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / genetics
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / immunology
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / metabolism
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Phenothiazines / pharmacology
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Primary Cell Culture
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Protease Inhibitors / pharmacology*
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Signal Transduction / drug effects
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Signal Transduction / immunology
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T-Lymphocytes, Cytotoxic / drug effects*
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / metabolism
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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Th1 Cells / drug effects
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Th1 Cells / immunology
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Th1 Cells / metabolism
Substances
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Phenothiazines
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Protease Inhibitors
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mepazine
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Interferon-gamma
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MALT1 protein, human
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Malt1 protein, mouse
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
Grants and funding
This study was funded by AstraZeneca. The authors were all employed by AstraZeneca AB during the course of the work described in the manuscript. AstraZeneca provided support in the form of salaries for authors [C. D., U.S., T.A., L.O., J.M., A, DeM, K.P., G.J., L.Y., R.J.C., F.S., M.H.L., U.G., A.M.D., O.V.], but did not have any additional role in the study involving design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.