RESUMEN
Objective: MALT1 regulates immunity and inflammation in multiple ways, while its role in rheumatoid arthritis (RA) is obscure. This study aimed to investigate the relationship of MALT1 with disease features, treatment outcome, as well as its effect on Th1/2/17 cell differentiation and underlying molecule mechanism in RA. Methods: Totally 147 RA patients were enrolled. Then their blood Th1, Th2, and Th17 cells were detected by flow cytometry. Besides, PBMC MALT1 expression was detected before treatment (baseline), at week (W) 6, W12, and W24. PBMC MALT1 in 30 osteoarthritis patients and 30 health controls were also detected. Then, blood CD4+ T cells were isolated from RA patients, followed by MALT1 overexpression or knockdown lentivirus transfection and Th1/2/17 polarization assay. In addition, IMD 0354 (NF-κB antagonist) and SP600125 (JNK antagonist) were also added to treat CD4+ T cells. Results: MALT1 was increased in RA patients compared to osteoarthritis patients and healthy controls. Meanwhile, MALT1 positively related to CRP, ESR, DAS28 score, Th17 cells, negatively linked with Th2 cells, but did not link with other features or Th1 cells in RA patients. Notably, MALT1 decreased longitudinally during treatment, whose decrement correlated with RA treatment outcome (treatment response, low disease activity, or disease remission). In addition, MALT1 overexpression promoted Th17 differentiation, inhibited Th2 differentiation, less affected Th1 differentiation, activated NF-κB and JNK pathways in RA CD4+ T cells; while MALT1 knockdown exhibited the opposite effect. Besides, IMD 0354 and SP600125 addition attenuated MALT1's effect on Th2 and Th17 differentiation. Conclusion: MALT1 regulates Th2 and Th17 differentiation via NF-κB and JNK pathways, as well as correlates with disease activity and treatment outcome in RA.
Asunto(s)
Artritis Reumatoide , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , FN-kappa B , Osteoartritis , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Diferenciación Celular , Humanos , Leucocitos Mononucleares/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , FN-kappa B/genética , FN-kappa B/inmunología , Osteoartritis/metabolismo , Células Th17/inmunología , Células Th2/inmunología , Resultado del TratamientoRESUMEN
Regulatory T cells (Tregs) are essential for the inhibition of immunity and the maintenance of tissue homeostasis. Signals from the T-cell antigen receptor (TCR) are critical for early Treg development, their expansion, and inhibitory activity. Although TCR-engaged activation of the paracaspase MALT1 is important for these Treg activities, the MALT1 effector pathways in Tregs remain ill-defined. Here, we demonstrate that MALT1 protease activity controls the TCR-induced upregulation of the transcription factor MYC and the subsequent expression of MYC target genes in Tregs. These mechanisms are important for Treg-intrinsic mitochondrial function, optimal respiratory capacity, and homeostatic Treg proliferation. Consistently, conditional deletion of Myc in Tregs results similar to MALT1 inactivation in a lethal autoimmune inflammatory syndrome. Together, these results identify a MALT1 protease-mediated link between TCR signaling in Tregs and MYC control that coordinates metabolism and Treg expansion for the maintenance of immune homeostasis.
Asunto(s)
Proliferación Celular , Activación de Linfocitos , Mitocondrias/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Proteínas Proto-Oncogénicas c-myc/inmunología , Linfocitos T Reguladores/inmunología , Animales , Ratones , Ratones Transgénicos , Mitocondrias/genética , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Proteínas Proto-Oncogénicas c-myc/genéticaRESUMEN
Nuclear factor kappa B (NF-κB) is a critical transcription factor involved in regulating cell activation, inflammation, and survival. The linear ubiquitin chain assembly complex (LUBAC) which consists of HOIL1, HOIP, and SHARPIN, catalyzes the linear ubiquitination of target proteins-a post-translational modification that is essential for NF-κB activation. Human germline pathogenic variants that dysregulate linear ubiquitination and NF-κB signaling are associated with immunodeficiency and/or autoinflammation including dermatitis, recurrent fevers, systemic inflammation and enteropathy. We previously identified MALT1 paracaspase as a novel negative regulator of LUBAC by proteolytic cleavage of HOIL1. To directly investigate the impact of HOIL1 cleavage activity on the inflammatory response, we employed a stable transduction system to express and directly compare non-cleavable HOIL1 with wild-type HOIL1 in primary HOIL1-deficient patient skin fibroblasts. We discovered that non-cleavable HOIL1 resulted in enhanced NF-κB signaling in response to innate stimuli. Transcriptomics revealed enrichment of inflammation and proinflammatory cytokine-related pathways after stimulation. Multiplexed cytokine assays confirmed a 'hyperinflammatory' phenotype in these cells. This work highlights the physiological importance of MALT1-dependent cleavage and modulation of HOIL1 on NF-κB signaling and inflammation, provides a mechanism for the autoinflammation observed in MALT1-deficient patients, and will inform the development of therapeutics that target MALT1 paracaspase and LUBAC function in treating autoinflammatory skin diseases.
Asunto(s)
Fibroblastos/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , FN-kappa B/inmunología , Factores de Transcripción/inmunología , Ubiquitina-Proteína Ligasas/inmunología , Citocinas/inmunología , Humanos , Inflamación/inmunología , Transducción de Señal , Factores de Transcripción/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Psoriasis is a chronic inflammatory skin disease arising from poorly defined pathological cross-talk between keratinocytes and the immune system. BCL10 (B cell lymphoma/leukemia 10) and MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) are ubiquitously expressed inflammatory signaling proteins that can interact with the psoriasis susceptibility factor CARD14, but their functions in psoriasis are insufficiently understood. We report that although keratinocyte-intrinsic BCL10/MALT1 deletions completely rescue inflammatory skin pathology triggered by germline Card14 gain-of-function mutation in mice, the BCL10/MALT1 signalosome is unexpectedly not involved in the CARD14-dependent interleukin-17 receptor (IL-17R) proximal pathway. Instead, it plays a more pleiotropic role by amplifying keratinocyte responses to a series of inflammatory cytokines, including IL-17A, IL-1ß, and TNF. Moreover, selective keratinocyte-intrinsic activation of BCL10/MALT1 signaling with an artificial engager molecule is sufficient to initiate lymphocyte-mediated psoriasiform skin inflammation, and aberrant BCL10/MALT1 activity is frequently detected in the skin of human sporadic psoriasis. Together, these results establish that BCL10/MALT1 signalosomes can act as initiators and crucial amplifiers of psoriatic skin inflammation and indicate a critical function for this complex in sporadic psoriasis.
Asunto(s)
Proteína 10 de la LLC-Linfoma de Células B/inmunología , Inflamación/inmunología , Queratinocitos/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Psoriasis/inmunología , Piel/inmunología , Animales , Proteína 10 de la LLC-Linfoma de Células B/deficiencia , Proteína 10 de la LLC-Linfoma de Células B/genética , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/deficiencia , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genéticaRESUMEN
Balanced control of T cell signaling is critical for adaptive immunity and protection from autoimmunity. By combining genetically engineered mouse models, biochemical analyses and pharmacological interventions, we describe an unexpected dual role of the tumor necrosis factor receptorassociated factor 6 (TRAF6) E3 ligase as both a positive and negative regulator of mucosa-associated lymphoid tissue 1 (MALT1) paracaspase. Although MALT1-TRAF6 recruitment is indispensable for nuclear factor κB signaling in activated T cells, TRAF6 counteracts basal MALT1 protease activity in resting T cells. In mice, loss of TRAF6-mediated homeostatic suppression of MALT1 protease leads to severe autoimmune inflammation, which is completely reverted by genetic or therapeutic inactivation of MALT1 protease function. Thus, TRAF6 functions as a molecular brake for MALT1 protease in resting T cells and a signaling accelerator for MALT1 scaffolding in activated T cells, revealing that TRAF6 controls T cell activation in a switch-like manner. Our findings have important implications for development and treatment of autoimmune diseases.
Asunto(s)
Homeostasis/inmunología , Inflamación/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Factor 6 Asociado a Receptor de TNF/inmunología , Animales , Femenino , Ratones , Ratones Endogámicos C57BL , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Factor 6 Asociado a Receptor de TNF/genéticaRESUMEN
Increasing evidence has supported the crucial role of CARD14 in the pathogenesis of psoriasis, whereas the precise cellular signaling involved in skin physiopathology remains poorly understood. In this article, we show that neither genetic ablation of Il17a nor elimination of T cells was sufficient to restrain the skin inflammation in a CARD14-E138A-mutation-induced psoriasis-like mouse model, whereas depletion of Il23, which extremely blocked the IL-23/T17 axis, was more effective. Targeting CBM complex by conditional deletion of MALT1 or BCL10 in keratinocytes abrogated both the cutaneous and systemic inflammation of heterozygous Card14 E138A/+ mice. Selective inactivation of keratinocyte-specific MALT1 proteolytic activity strongly ameliorated the Card14 E138A/+- and Card14 ΔQ136/+-induced skin disease, which was reproduced by using the imiquimod-induced mouse model. Together, our results suggest a sequence of events under CARD14-mutation-induced psoriasis condition that keratinocyte-intrinsic activation of CBM complex initiates the skin inflammation depending on the IL-23/T17 axis. Targeting keratinocytes by inactivation of MALT1 paracaspase activity might be a promising therapeutic target for early psoriasis treatment.
Asunto(s)
Interleucina-23/inmunología , Queratinocitos/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Psoriasis/inmunología , Piel/inmunología , Células Th17/inmunología , Animales , Línea Celular , Modelos Animales de Enfermedad , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Interleucina-23/genética , Queratinocitos/patología , Ratones , Ratones Noqueados , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Psoriasis/genética , Psoriasis/patología , Piel/patología , Células Th17/patologíaRESUMEN
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-É£) 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-É£, in a mouse model of acute T-cell activation, and long-term treatment did not lead to an increase in IFN-É£ 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.
Asunto(s)
Linfocitos B/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/antagonistas & inhibidores , Inhibidores de Proteasas/farmacología , Linfocitos T Citotóxicos/efectos de los fármacos , Regulación Alostérica/efectos de los fármacos , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Células Cultivadas , Células Dendríticas/inmunología , Femenino , Transferencia Resonante de Energía de Fluorescencia , Voluntarios Sanos , Humanos , Inyecciones Intraperitoneales , Interferón gamma/inmunología , Interferón gamma/metabolismo , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Noqueados , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Fenotiazinas/farmacología , Cultivo Primario de Células , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/metabolismoRESUMEN
T cell responses to antigen are initiated by engagement of the T cell receptor (TCR)1, leading to activation of diverse signaling cascades, including an incompletely defined pathway that triggers rapid remodeling of the actin cytoskeleton. Defects in the control of actin dynamics and organization are associated with several human immunodeficiency diseases, emphasizing the importance of cytoskeletal remodeling in the functioning of the adaptive immune system. Here, we investigate the role of the adaptor protein Bcl102 in the control of actin dynamics. Although Bcl10 is primarily known as a component of the pathway connecting the TCR to activation of the NF-κB3 transcription factor, a few studies have implicated Bcl10 in antigen receptor-dependent control of actin polymerization and F-actin-dependent functional responses. However, the role of Bcl10 in the regulation of cytoskeletal dynamics remains largely undefined. To investigate the contribution of Bcl10 in the regulation of TCR-dependent cytoskeletal dynamics, we monitored actin dynamics at the immune synapse of primary murine CD8 effector T cells. Quantification of these dynamics reveals two distinct temporal phases distinguished by differences in speed and directionality. Our results indicate that effector CD8 T cells lacking Bcl10 display faster actin flows and more dynamic lamellipodia, compared to wild-type cells. These studies define a role for Bcl10 in TCR-dependent actin dynamics, emphasizing that Bcl10 has important cytoskeleton-directed functions that are likely independent of its role in transmission of NF-κB -activating signals.
Asunto(s)
Actinas/metabolismo , Proteína 10 de la LLC-Linfoma de Células B/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Actinas/inmunología , Animales , Proteína 10 de la LLC-Linfoma de Células B/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , FN-kappa B/inmunología , FN-kappa B/metabolismo , Fosforilación , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal/inmunología , Sinapsis/metabolismoRESUMEN
The signaling protein MALT1 plays a key role in promoting NF-κB activation in Ag-stimulated lymphocytes. In this capacity, MALT1 has two functions, acting as a scaffolding protein and as a substrate-specific protease. MALT1 is also required for NF-κB-dependent induction of proinflammatory cytokines after FcεR1 stimulation in mast cells, implicating a role in allergy. Because MALT1 remains understudied in this context, we sought to investigate how MALT1 proteolytic activity contributes to the overall allergic response. We compared bone marrow-derived mast cells from MALT1 knockout (MALT1-/-) and MALT1 protease-deficient (MALTPD/PD) mice to wild-type cells. We found that MALT1-/- and MALT1PD/PD mast cells are equally impaired in cytokine production following FcεRI stimulation, indicating that MALT1 scaffolding activity is insufficient to drive the cytokine response and that MALT1 protease activity is essential. In addition to cytokine production, acute mast cell degranulation is a critical component of allergic response. Intriguingly, whereas degranulation is MALT1-independent, MALT1PD/PD mice are protected from vascular edema induced by either passive cutaneous anaphylaxis or direct challenge with histamine, a major granule component. This suggests a role for MALT1 protease activity in endothelial cells targeted by mast cell-derived vasoactive substances. Indeed, we find that in human endothelial cells, MALT1 protease is activated following histamine treatment and is required for histamine-induced permeability. We thus propose a dual role for MALT1 protease in allergic response, mediating 1) IgE-dependent mast cell cytokine production, and 2) histamine-induced endothelial permeability. This dual role indicates that therapeutic inhibitors of MALT1 protease could work synergistically to control IgE-mediated allergic disease.
Asunto(s)
Células Endoteliales/metabolismo , Hipersensibilidad/metabolismo , Mastocitos/metabolismo , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Animales , Médula Ósea/inmunología , Médula Ósea/metabolismo , Línea Celular , Citocinas/inmunología , Citocinas/metabolismo , Células Endoteliales/inmunología , Femenino , Histamina/inmunología , Humanos , Hipersensibilidad/inmunología , Inmunoglobulina E/inmunología , Inmunoglobulina E/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Activación de Linfocitos/inmunología , Mastocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , FN-kappa B/inmunología , FN-kappa B/metabolismo , Receptores de IgE/inmunología , Receptores de IgE/metabolismoRESUMEN
OBJECTIVE: Fcγ receptors (FcγR) play important roles in both protective and pathogenic immune responses. The assembly of the CBM signalosome encompassing caspase recruitment domain-containing protein 9, B cell CLL/lymphoma 10, and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT-1) is required for optimal FcγR-induced canonical NF-κB activation and proinflammatory cytokine release. This study was undertaken to clarify the relevance of MALT-1 protease activity in FcγR-driven events and evaluate the therapeutic potential of selective MALT-1 protease inhibitors in FcγR-mediated diseases. METHODS: Using genetic and pharmacologic disruption of MALT-1 scaffolding and enzymatic activity, we assessed the relevance of MALT-1 function in murine and human primary myeloid cells upon stimulation with immune complexes (ICs) and in murine models of autoantibody-driven arthritis and immune thrombocytopenic purpura (ITP). RESULTS: MALT-1 protease function is essential for optimal FcγR-induced production of proinflammatory cytokines by various murine and human myeloid cells stimulated with ICs. In contrast, MALT-1 protease inhibition did not affect the Syk-dependent, FcγR-mediated production of reactive oxygen species or leukotriene B4 . Notably, pharmacologic MALT-1 protease inhibition in vivo reduced joint inflammation in the murine K/BxN serum-induced arthritis model (mean area under the curve for paw swelling of 45.42% versus 100% in control mice; P = 0.0007) but did not affect platelet depletion in a passive model of ITP. CONCLUSION: Our findings indicate a specific contribution of MALT-1 protease activity to FcγR-mediated events and suggest that MALT-1 protease inhibitors have therapeutic potential in a subset of FcγR-driven inflammatory disorders.
Asunto(s)
Artritis Experimental/inmunología , Artritis Reumatoide/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Receptores de IgG/inmunología , Animales , Complejo Antígeno-Anticuerpo/metabolismo , Plaquetas/metabolismo , Citocinas/inmunología , Modelos Animales de Enfermedad , Humanos , Ratones , Células Mieloides/metabolismoRESUMEN
The paracaspase Malt1 is a key regulator of canonical NF-κB activation downstream of multiple receptors in both immune and nonimmune cells. Genetic disruption of Malt1 protease function in mice and MALT1 mutations in humans results in reduced regulatory T cells and a progressive multiorgan inflammatory pathology. In this study, we evaluated the altered immune homeostasis and autoimmune disease in Malt1 protease-deficient (Malt1PD) mice and the Ags driving disease manifestations. Our data indicate that B cell activation and IgG1/IgE production is triggered by microbial and dietary Ags preferentially in lymphoid organs draining mucosal barriers, likely as a result of dysregulated mucosal immune homeostasis. Conversely, the disease was driven by a polyclonal T cell population directed against self-antigens. Characterization of the Malt1PD T cell compartment revealed expansion of T effector memory cells and concomitant loss of a CD4+ T cell population that phenotypically resembles anergic T cells. Therefore, we propose that the compromised regulatory T cell compartment in Malt1PD animals prevents the efficient maintenance of anergy and supports the progressive expansion of pathogenic, IFN-γ-producing T cells. Overall, our data revealed a crucial role of the Malt1 protease for the maintenance of intestinal and systemic immune homeostasis, which might provide insights into the mechanisms underlying IPEX-related diseases associated with mutations in MALT1.
Asunto(s)
Autoinmunidad/inmunología , Homeostasis/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Linfocitos T Reguladores/inmunología , Animales , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/deficiencia , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genéticaRESUMEN
MALT1 is a central signaling component in innate and adaptive immunity by regulating NF-κB and other key signaling pathways in different cell types. Activities of MALT1 are mediated by its scaffold and protease functions. Because of its role in lymphocyte activation and proliferation, inhibition of MALT1 proteolytic activity is of high interest for therapeutic targeting in autoimmunity and certain lymphomas. However, recent studies showing that Malt1 protease-dead knock-in (Malt1-PD) mice suffer from autoimmune disease have somewhat tempered the initial enthusiasm. Although it has been proposed that an imbalance between immune suppressive regulatory T cells (Tregs) and activated effector CD4+ T cells plays a key role in the autoimmune phenotype of Malt1-PD mice, the specific contribution of MALT1 proteolytic activity in T cells remains unclear. Using T cell-conditional Malt1 protease-dead knock-in (Malt1-PDT) mice, we here demonstrate that MALT1 has a T cell-intrinsic role in regulating the homeostasis and function of thymic and peripheral T cells. T cell-specific ablation of MALT1 proteolytic activity phenocopies mice in which MALT1 proteolytic activity has been genetically inactivated in all cell types. The Malt1-PDT mice have a reduced number of Tregs in the thymus and periphery, although the effect in the periphery is less pronounced compared to full-body Malt1-PD mice, indicating that also other cell types may promote Treg induction in a MALT1 protease-dependent manner. Despite the difference in peripheral Treg number, both T cell-specific and full-body Malt1-PD mice develop ataxia and multi-organ inflammation to a similar extent. Furthermore, reconstitution of the full-body Malt1-PD mice with T cell-specific expression of wild-type human MALT1 eliminated all signs of autoimmunity. Together, these findings establish an important T cell-intrinsic role of MALT1 proteolytic activity in the suppression of autoimmune responses.
Asunto(s)
Autoinmunidad/inmunología , Activación de Linfocitos/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Linfocitos T/inmunología , Animales , Autoinmunidad/genética , Homeostasis/genética , Homeostasis/inmunología , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Activación de Linfocitos/genética , Ratones Noqueados , Ratones Transgénicos , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Proteolisis , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Timo/citología , Timo/inmunología , Timo/metabolismoRESUMEN
Regulatory T cells (Tregs) have crucial functions in the inhibition of immune responses. Their development and suppressive functions are controlled by the T cell receptor (TCR), but the TCR signaling mechanisms that mediate these effects remain ill-defined. Here we show that CARD11-BCL10-MALT1 (CBM) signaling mediates TCR-induced NF-κB activation in Tregs and controls the conversion of resting Tregs to effector Tregs under homeostatic conditions. However, in inflammatory milieus, cytokines can bypass the CBM requirement for this differentiation step. By contrast, CBM signaling, in a MALT1 protease-dependent manner, is essential for mediating the suppressive function of Tregs. In malignant melanoma models, acute genetic blockade of BCL10 signaling selectively in Tregs or pharmacological MALT1 inhibition enhances anti-tumor immune responses. Together, our data uncover a segregation of Treg differentiation and suppressive function at the CBM complex level, and provide a rationale to explore MALT1 inhibitors for cancer immunotherapy.
Asunto(s)
Proteína 10 de la LLC-Linfoma de Células B/inmunología , Proteínas Adaptadoras de Señalización CARD/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Animales , Proteína 10 de la LLC-Linfoma de Células B/metabolismo , Proteínas Adaptadoras de Señalización CARD/metabolismo , Diferenciación Celular , Citocinas/inmunología , Melanoma Experimental , Ratones , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , FN-kappa B/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismoRESUMEN
The paracaspase Malt1 is a key molecule in mediating Ag receptor-induced NF-κB activation in lymphocytes, but the role of Malt1 in the function of regulatory T (Treg) cells is still unclear. In this article, we reported that specific deletion of Malt1 in Treg cells would lead to Scurfy-like lethal autoimmune disease, which was caused by Treg cell dysfunction but not number loss. Interestingly, Foxp3CreMalt1fl/C472A mice, in which Malt1 protease was specifically inactivated in Treg cells, also displayed spontaneous inflammatory disorders, with severe hair loss and skin hyperplasia. Consistently, Foxp3CreMalt1fl/C472A mice showed enhanced antitumor response because of their decreased function and infiltration of Treg cells, as well as reduced CD8+ T cell exhaustion. Gene expression profiling analysis revealed dysregulated expression pattern of Treg effector genes upon Malt1 deletion or its protease inactivation. Together, our data unraveled a critical role of Malt1, especially its protease activity, in maintaining homeostasis and function of Treg cells.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Neoplasias Cutáneas/inmunología , Linfocitos T Reguladores/inmunología , Animales , Linfocitos T CD8-positivos/patología , Hiperplasia , Linfocitos Infiltrantes de Tumor/patología , Ratones , Ratones Noqueados , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Linfocitos T Reguladores/patologíaRESUMEN
OBJECTIVE AND DESIGN: Protease activity of MALT lymphoma-translocation protein 1 (Malt1) plays an important role in the development of colitis, but the detailed mechanism has not been fully elucidated. METHOD: Effects of Malt1 protease on the activation of T cells and the development of experimental colitis was investigated using Malt1 protease-deficient (PD) mouse. RESULTS: IL-2 production from CD4+ T cells of Malt1 PD mice was decreased compared with that of wild-type (WT) mice. Intraperitoneal injection of anti-CD3 antibody into Malt1 PD mouse induced less productions of IL-17 in the plasma, as well as the colonic gene expression of IL-17A, compared with WT mice, whereas IFN-γ production was not impaired. In naïve T-cell transfer colitis model, Malt1 PD T cells induced less disease severity than WT T cells. Then, reduction in the populations of Th17 and Th1/17 cells was observed in the mesenteric lymph nodes of the recipient mice transferred with Malt1 PD T cells, whereas those of Th1 cells were not impaired. IL-17A expression in the colon was also decreased in the mouse receiving Malt1 PD T cells. CONCLUSIONS: Inactivation of Malt1 protease activity abrogates Th17 and Th1/17 cell activation, resulting in the amelioration of experimental colitis.
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Linfocitos T CD4-Positivos/inmunología , Citocinas/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Traslado Adoptivo , Animales , Linfocitos T CD4-Positivos/trasplante , Colitis/inmunología , Colon/inmunología , Femenino , Ganglios Linfáticos/inmunología , Ratones Endogámicos BALB C , Ratones SCIDRESUMEN
Antigen receptor-induced signaling plays an important role in inflammation and immunity. Formation of a CARD11-BCL10-MALT1 (CBM) signaling complex is a key event in T- and B cell receptor-induced gene expression by regulating NF-κB activation and mRNA stability. Deregulated CARD11, BCL10 or MALT1 expression or CBM signaling have been associated with immunodeficiency, autoimmunity and cancer, indicating that CBM formation and function have to be tightly regulated. Over the past years great progress has been made in deciphering the molecular mechanisms of assembly and disassembly of the CBM complex. In this context, several posttranslational modifications play an indispensable role in regulating CBM function and downstream signal transduction. In this review we summarize how the different CBM components as well as their interplay are regulated by protein ubiquitination and phosphorylation in the context of T cell receptor signaling.
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Enfermedades Autoinmunes/genética , Proteína 10 de la LLC-Linfoma de Células B/genética , Proteínas Adaptadoras de Señalización CARD/genética , Guanilato Ciclasa/genética , Síndromes de Inmunodeficiencia/genética , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Neoplasias/genética , Procesamiento Proteico-Postraduccional/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Proteína 10 de la LLC-Linfoma de Células B/inmunología , Linfocitos B/inmunología , Linfocitos B/patología , Proteínas Adaptadoras de Señalización CARD/inmunología , Guanilato Ciclasa/inmunología , Humanos , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/patología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , FN-kappa B/genética , FN-kappa B/inmunología , Neoplasias/inmunología , Neoplasias/patología , Fosforilación , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/inmunología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/patología , UbiquitinaciónRESUMEN
CARD protein-BCL-10-MALT1 (CBM) signalosomes are multiprotein signalling platforms that control immune and inflammatory pathways in most tissues. After exposure to distinct immune triggers, these molecules form self-organizing filaments with MALT1 protease activity to regulate canonical nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signalling pathways and the degradation of mRNA-binding proteins, which provides two layers of control of inflammatory gene expression. These CBM-regulated mechanisms are essential for host defence and tissue homeostasis, and numerous genetic alterations in CBM signalling components have been implicated in inherited and acquired immune-mediated diseases. This Review discusses the regulation and signalling of CBM complexes, their physiological roles and their pathophysiological functions in human immunodeficiency diseases, inflammatory disorders and cancers of the immune system.
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Proteína 10 de la LLC-Linfoma de Células B/inmunología , Proteínas Adaptadoras de Señalización CARD/metabolismo , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Transducción de Señal/inmunología , Animales , Humanos , Síndromes de Inmunodeficiencia/inmunología , Inflamación/inmunología , FN-kappa B/inmunologíaRESUMEN
The CARD: BCL10: MALT1 (CBM) complex is an essential signaling node for maintaining both innate and adaptive immune responses. CBM complex components have gained considerable interest due to the dramatic effects of associated mutations in causing severe lymphomas, immunodeficiencies, carcinomas and inflammatory disease. While MALT1 and BCL10 are ubiquitous proteins, the CARD-containing proteins differ in their tissue expression. CARD14 is primarily expressed in keratinocytes. The CARD14-BCL10-MALT1 complex is activated by upstream pathogen-associated molecular pattern-recognition in vitro, highlighting a potentially crucial role in innate immune defense at the epidermal barrier. Recent findings have demonstrated how CARD14 orchestrates activation of the NF-κB and MAPK signaling pathways via recruitment of BCL10 and MALT1, leading to the upregulation of pro-inflammatory genes encoding IL-36γ, IL-8, Ccl20 and anti-microbial peptides. Following the identification of CARD14 gain-of function mutations as responsible for the psoriasis susceptibility locus PSORS2, the past years have witnessed a large volume of case reports and association studies describing CARD14 variants as causal or predisposing to a wide range of inflammatory skin disorders. Recent publications of mouse models also helped to better understand the physiological contribution of CARD14 to psoriasis pathogenesis. In this review, we summarize the clinical, genetic and functional aspects of human and murine CARD14 mutations and their contribution to psoriatic disease pathogenesis.
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Proteínas Adaptadoras de Señalización CARD/inmunología , Heterogeneidad Genética , Guanilato Ciclasa/inmunología , Proteínas de la Membrana/inmunología , Mutación , Psoriasis/inmunología , Animales , Proteína 10 de la LLC-Linfoma de Células B/genética , Proteína 10 de la LLC-Linfoma de Células B/inmunología , Proteína 10 de la LLC-Linfoma de Células B/metabolismo , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/metabolismo , Guanilato Ciclasa/genética , Guanilato Ciclasa/metabolismo , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Psoriasis/genética , Psoriasis/metabolismo , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
Pathogen immune responses are profoundly attenuated in fetuses and premature infants, yet the mechanisms underlying this developmental immaturity remain unclear. Here we show transcriptomic, metabolic and polysome profiling and find that monocytes isolated from infants born early in gestation display perturbations in PPAR-γ-regulated metabolic pathways, limited glycolytic capacity and reduced ribosomal activity. These metabolic changes are linked to a lack of translation of most cytokines and of MALT1 signalosome genes essential to respond to the neonatal pathogen Candida. In contrast, they have little impact on house-keeping phagocytosis functions. Transcriptome analyses further indicate a role for mTOR and its putative negative regulator DNA Damage Inducible Transcript 4-Like in regulating these metabolic constraints. Our results provide a molecular basis for the broad susceptibility to multiple pathogens in these infants, and suggest that the fetal immune system is metabolically programmed to avoid energetically costly, dispensable and potentially harmful immune responses during ontogeny.
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Regulación del Desarrollo de la Expresión Génica , Inmunidad Innata , Monocitos/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , PPAR gamma/inmunología , Factores de Transcripción/inmunología , Adulto , Proteína 10 de la LLC-Linfoma de Células B/deficiencia , Proteína 10 de la LLC-Linfoma de Células B/genética , Proteína 10 de la LLC-Linfoma de Células B/inmunología , Proteínas Adaptadoras de Señalización CARD/deficiencia , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/inmunología , Candida albicans/inmunología , Candida parapsilosis/inmunología , Humanos , Recién Nacido , Recien Nacido Prematuro , Interleucinas/deficiencia , Interleucinas/genética , Interleucinas/inmunología , Lectinas Tipo C/deficiencia , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Lipopolisacáridos/farmacología , Análisis por Micromatrices , Monocitos/citología , Monocitos/efectos de los fármacos , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/deficiencia , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , PPAR gamma/deficiencia , PPAR gamma/genética , Cultivo Primario de Células , Biosíntesis de Proteínas/inmunología , Serina-Treonina Quinasas TOR/deficiencia , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/inmunología , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Transcriptoma/inmunología , Factor de Necrosis Tumoral alfa/deficiencia , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
The caspase recruitment domain family member 11 (CARD11 or CARMA1)-B cell CLL/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) [CBM] signalosome complex serves as a molecular bridge between cell surface antigen receptor signaling and the activation of the NF-κB, JNK, and mTORC1 signaling axes. This positions the CBM complex as a critical regulator of lymphocyte activation, proliferation, survival, and metabolism. Inborn errors in each of the CBM components have now been linked to a diverse group of human primary immunodeficiency diseases termed "CBM-opathies." Clinical manifestations range from severe combined immunodeficiency to selective B cell lymphocytosis, atopic disease, and specific humoral defects. This surprisingly broad spectrum of phenotypes underscores the importance of "tuning" CBM signaling to preserve immune homeostasis. Here, we review the distinct clinical and immunological phenotypes associated with human CBM complex mutations and introduce new avenues for targeted therapeutic intervention.