A MALT1 inhibitor suppresses human myeloid DC, effector T-cell and B-cell responses and retains Th1/regulatory T-cell homeostasis

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 Tcell 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 Tcell 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.

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

“…As a crucial regulator, MALT1 activates nuclear factor‐kappa‐B (NF‐κB) signaling pathway to induce signaling‐mediated macrophage activation and further promotes the inflammatory response 19,20 . In addition, MALT1 is involved in inducing and promoting the differentiation of T‐helper 1 (Th1) and T‐helper 17 (Th17) cells, which aggravates many inflammatory and autoimmune diseases 21‐24 . Besides, considering that RA is a chronic autoimmune disease, we assumed that MALT1 might serve as a novel biomarker for RA.…”

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

“…Previous studies indicate that MALT1 regulates CD4 + T‐cell differentiation into Th1 and 17 cells, and their effector response based on in vitro study 12 . Meanwhile, in vivo, the MALT1 deficiency colitis mouse model displayed a reduction of the Th17 cell amount and IL‐17A (Th17 cell secreted cytokines) 11 .…”

“…Furthermore, apart from that, MALT1 enhances vascular inflammation and endothelial barrier disruption in several studies 14‐17 . Because MALT1 may enhance inflammatory cytokine production in endothelial cells and induce endothelial dysfunction, and these physiological changes indicate further atherosclerosis, thrombosis formation, and AIS occurrence and also MALT1 regulates Th cell differentiation and their related inflammatory cytokine excretion; therefore, we hypothesized that MALT1 measurement might play a pivotal role for AIS management 10‐12,18‐20 . In our preliminary study with a relatively small sample size, we discovered that MALT1 was increased in AIS patients compared with controls.…”

“…Mucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key mediator in the nuclear factor (NF)‐κB signaling pathway which is involved in lymphocyte activation, proliferation, and survival via its link to different receptors 7‐9 . Meanwhile, previous studies disclose that MALT1 regulates a cluster of differentiation 4‐positive (CD4 + ) T‐cell differentiation into T helper type 1 (Th1) cells and Th17 cells 10‐13 . Furthermore, apart from that, MALT1 enhances vascular inflammation and endothelial barrier disruption in several studies 14‐17 .…”

“…[7][8][9] Meanwhile, previous studies disclose that MALT1 regulates a cluster of differentiation 4-positive (CD4 + ) T-cell differentiation into T helper type 1 (Th1) cells and Th17 cells. [10][11][12][13] Furthermore, apart from that, MALT1 enhances vascular inflammation and endothelial barrier disruption in several studies. [14][15][16][17] Because MALT1 may enhance inflammatory cytokine production in endothelial cells and induce endothelial dysfunction, and these physiological changes indicate further atherosclerosis, thrombosis formation, and AIS occurrence and also MALT1 regulates Th cell differentiation and their related inflammatory cytokine excretion; therefore, we hypothesized that MALT1 measurement might play a pivotal role for AIS management.…”