RESUMEN
Cell-cell communication involves a large number of molecular signals that function as words of a complex language whose grammar remains mostly unknown. Here, we describe an integrative approach involving (1) protein-level measurement of multiple communication signals coupled to output responses in receiving cells and (2) mathematical modeling to uncover input-output relationships and interactions between signals. Using human dendritic cell (DC)-T helper (Th) cell communication as a model, we measured 36 DC-derived signals and 17 Th cytokines broadly covering Th diversity in 428 observations. We developed a data-driven, computationally validated model capturing 56 already described and 290 potentially novel mechanisms of Th cell specification. By predicting context-dependent behaviors, we demonstrate a new function for IL-12p70 as an inducer of Th17 in an IL-1 signaling context. This work provides a unique resource to decipher the complex combinatorial rules governing DC-Th cell communication and guide their manipulation for vaccine design and immunotherapies.
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Comunicación Celular/inmunología , Células Dendríticas/inmunología , Interleucina-12/fisiología , Células Th17/inmunología , Adolescente , Adulto , Anciano , Células Cultivadas , Técnicas de Cocultivo , Voluntarios Sanos , Humanos , Interleucina-1/metabolismo , Persona de Mediana Edad , Modelos Biológicos , Adulto JovenRESUMEN
T helper type 2 (Th2) cells are important regulators of mammalian adaptive immunity and have relevance for infection, autoimmunity, and tumor immunology. Using a newly developed, genome-wide retroviral CRISPR knockout (KO) library, combined with RNA-seq, ATAC-seq, and ChIP-seq, we have dissected the regulatory circuitry governing activation and differentiation of these cells. Our experiments distinguish cell activation versus differentiation in a quantitative framework. We demonstrate that these two processes are tightly coupled and are jointly controlled by many transcription factors, metabolic genes, and cytokine/receptor pairs. There are only a small number of genes regulating differentiation without any role in activation. By combining biochemical and genetic data, we provide an atlas for Th2 differentiation, validating known regulators and identifying factors, such as Pparg and Bhlhe40, as part of the core regulatory network governing Th2 helper cell fates.
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Receptor Cross-Talk/inmunología , Células Th2/inmunología , Células Th2/metabolismo , Animales , Sistemas CRISPR-Cas/genética , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Cromatina , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Genoma , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Linfocitos T Colaboradores-Inductores/metabolismo , Factores de Transcripción/metabolismoRESUMEN
The development and function of the immune system are controlled by temporospatial gene expression programs, which are regulated by cis-regulatory elements, chromatin structure, and trans-acting factors. In this study, we cataloged the dynamic histone modifications and chromatin interactions at regulatory regions during T helper (Th) cell differentiation. Our data revealed that the H3K4me1 landscape established by MLL4 in naive CD4+ T cells is critical for restructuring the regulatory interaction network and orchestrating gene expression during the early phase of Th differentiation. GATA3 plays a crucial role in further configuring H3K4me1 modification and the chromatin interaction network during Th2 differentiation. Furthermore, we demonstrated that HSS3-anchored chromatin loops function to restrict the activity of the Th2 locus control region (LCR), thus coordinating the expression of Th2 cytokines. Our results provide insights into the mechanisms of how the interplay between histone modifications, chromatin looping, and trans-acting factors contributes to the differentiation of Th cells.
Asunto(s)
Diferenciación Celular , Cromatina , Código de Histonas , Histonas , Células Th2 , Diferenciación Celular/inmunología , Animales , Cromatina/metabolismo , Ratones , Células Th2/inmunología , Histonas/metabolismo , Factor de Transcripción GATA3/metabolismo , Regulación de la Expresión Génica , Ratones Endogámicos C57BL , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Región de Control de Posición , Citocinas/metabolismoRESUMEN
Interleukin-23 receptor plays a critical role in inducing inflammation and autoimmunity. Here, we report that Th1-like cells differentiated in vitro with IL-12 + IL-21 showed similar IL-23R expression to that of pathogenic Th17 cells using eGFP reporter mice. Fate mapping established that these cells did not transition through a Th17 cell state prior to becoming Th1-like cells, and we observed their emergence in vivo in the T cell adoptive transfer colitis model. Using IL-23R-deficient Th1-like cells, we demonstrated that IL-23R was required for the development of a highly colitogenic phenotype. Single-cell RNA sequencing analysis of intestinal T cells identified IL-23R-dependent genes in Th1-like cells that differed from those expressed in Th17 cells. The perturbation of one of these regulators (CD160) in Th1-like cells inhibited the induction of colitis. We thus uncouple IL-23R as a purely Th17 cell-specific factor and implicate IL-23R signaling as a pathogenic driver in Th1-like cells inducing tissue inflammation.
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Colitis , Receptores de Interleucina , Animales , Inflamación/metabolismo , Interleucina-23/metabolismo , Ratones , Ratones Endogámicos C57BL , Fenotipo , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Células TH1 , Células Th17RESUMEN
Upon activation, naive CD4+ T cells differentiate into distinct T cell subsets via processes reliant on epigenetically regulated, lineage-specific developmental programs. Here, we examined the function of the histone methyltransferase SETDB1 in T helper (Th) cell differentiation. Setdb1-/- naive CD4+ T cells exhibited exacerbated Th1 priming, and when exposed to a Th1-instructive signal, Setdb1-/- Th2 cells crossed lineage boundaries and acquired a Th1 phenotype. SETDB1 did not directly control Th1 gene promoter activity but relied instead on deposition of the repressive H3K9me3 mark at a restricted and cell-type-specific set of endogenous retroviruses (ERVs) located in the vicinity of genes involved in immune processes. Refined bioinformatic analyses suggest that these retrotransposons regulate Th1 gene cis-regulatory elements or act as Th1 gene enhancers. Thus, H3K9me3 deposition by SETDB1 ensures Th cell lineage integrity by repressing a repertoire of ERVs that have been exapted into cis-regulatory modules to shape and control the Th1 gene network.
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Linaje de la Célula/inmunología , Retrovirus Endógenos/inmunología , Histona Metiltransferasas/inmunología , N-Metiltransferasa de Histona-Lisina/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular/inmunología , Femenino , Histonas/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas/inmunología , Células TH1/inmunología , Células Th2/inmunologíaRESUMEN
Live vaccines historically afford superior protection, yet the cellular and molecular mechanisms mediating protective immunity remain unclear. Here we found that vaccination of mice with live, but not dead, Gram-negative bacteria heightened follicular T helper cell (Tfh) differentiation, germinal center formation, and protective antibody production through the signaling adaptor TRIF. Complementing the dead vaccine with an innate signature of bacterial viability, bacterial RNA, recapitulated these responses. The interferon (IFN) and inflammasome pathways downstream of TRIF orchestrated Tfh responses extrinsically to B cells and classical dendritic cells. Instead, CX3CR1+CCR2- monocytes instructed Tfh differentiation through interleukin-1ß (IL-1ß), a tightly regulated cytokine secreted upon TRIF-dependent IFN licensing of the inflammasome. Hierarchical production of IFN-ß and IL-1ß dictated Tfh differentiation and elicited the augmented humoral responses characteristic of live vaccines. These findings identify bacterial RNA, an innate signature of microbial viability, as a trigger for Tfh differentiation and suggest new approaches toward vaccine formulations for coordinating augmented Tfh and B cell responses.
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Formación de Anticuerpos/inmunología , Linfocitos B/inmunología , Activación de Linfocitos/inmunología , Viabilidad Microbiana/inmunología , ARN Bacteriano/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Proteínas Adaptadoras del Transporte Vesicular/inmunología , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Animales , Anticuerpos Neutralizantes/inmunología , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Linfocitos B/metabolismo , Vacunas Bacterianas/inmunología , Biomarcadores , Diferenciación Celular/inmunología , Citocinas/metabolismo , Centro Germinal , Interacciones Huésped-Patógeno/inmunología , Inmunidad Celular , Inmunidad Innata , Inflamasomas/metabolismo , Ratones , Monocitos/inmunología , Monocitos/metabolismo , Receptor de Interferón alfa y beta/genética , Receptor de Interferón alfa y beta/metabolismo , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/metabolismo , Transducción de Señal , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, also called APS-1) is an inborn error of immunity with clear signs of B-cell autoimmunity such as neutralizing anti-IFN antibodies. In APECED, mutations in the AIRE gene impair thymic negative selection of T cells. The resulting T-cell alterations may then cause dysregulation of B-cell responses. However, no analysis of interactions of T and B cells in the germinal centers (GCs) in patients' secondary lymphatic tissues has been reported. OBJECTIVE: This study examined the relationship between B cells and follicular T helper cells (TfH) in peripheral blood and lymph node (LN) GCs in patients with APECED. METHODS: Immunophenotyping of peripheral blood B cells and TfH was performed for 24 patients with APECED. Highly multiplexed fluorescent immunohistochemical staining was performed on 7 LN biopsy samples from the patients to study spatial interactions of lymphocytes in the GCs at the single-cell level. RESULTS: The patients' peripheral B-cell phenotype revealed skewing toward a mature B-cell phenotype with marked loss of transitional and naive B cells. The frequency of circulating TfH cells was diminished in the patients, while in the LNs the TfH population was expanded. In LNs the overall frequency of Treg cells and interactions of Treg cells with nonfollicular T cells were reduced, suggesting that aberrant Treg cell function might fail to restrain TfH differentiation. CONCLUSIONS: GC reactions are disrupted in APECED as a result of defective T-cell control.
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Linfocitos B , Centro Germinal , Ganglios Linfáticos , Poliendocrinopatías Autoinmunes , Células T Auxiliares Foliculares , Humanos , Poliendocrinopatías Autoinmunes/inmunología , Poliendocrinopatías Autoinmunes/genética , Centro Germinal/inmunología , Femenino , Masculino , Linfocitos B/inmunología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Adulto , Células T Auxiliares Foliculares/inmunología , Adolescente , Niño , Adulto Joven , Persona de Mediana Edad , Inmunofenotipificación , Proteína AIRE , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
Serum amyloid A (SAA) is a clinically useful inflammatory marker involved in the pathogenesis of autoimmune diseases. This study aimed to explore the SAA levels in a cohort of patients with myasthenia gravis (MG) in relation to disease-related clinical parameters and myasthenic crisis (MC) and elucidate the effects of SAA on immune response. A total of 82 MG patients including 50 new-onset MG patients and 32 MC patients were enrolled in this study. Baseline data and laboratory parameters of all enrolled MG patients were routinely recorded through electronic medical systems. SAA levels were measured by enzyme-linked immunosorbent assay (ELISA) kit. CD4+ T and CD19+ B cell subsets were analyzed by flow cytometry. In vitro, human recombinant SAA (Apo-SAA) was applied to stimulate peripheral blood mononuclear cells (PBMCs) from MG patients to observe the effect on T and B cell differentiation. Our results indicated that SAA levels in new-onset MG patients were higher than those in controls and were positively correlated with QMG score, MGFA classification, plasmablast cells, IL-6, and IL-17 levels. Subgroup analysis revealed that SAA levels were increased in generalized MG (GMG) patients than in ocular MG (OMG), as well as elevated in late-onset MG (LOMG) than in early-onset MG (EOMG) and higher in MGFA III/IV compared with MGFA I/II. The ROC curve demonstrated that SAA showed good diagnostic value for MC, especially when combined with NLR. In vitro, Apo-SAA promoted the Th1 cells, Th17 cells, plasmablast cells, and plasma cells differentiation in MG PBMCs. The present findings suggested that SAA was increased in MG patients and promoted expansion of CD4+ T cell and CD19+ B cell subsets, which implicated in the severity of MG patients.
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Subgrupos de Linfocitos B , Miastenia Gravis , Humanos , Leucocitos Mononucleares , Miastenia Gravis/diagnóstico , Proteína Amiloide A Sérica , Células TH1RESUMEN
Chronic hepatitis B virus (HBV) infection is a significant global public health concern, and the clearance of HBV is closely linked to the activity of HBV-specific T cells, which is regulated by various co-suppressor molecules. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is among these co-suppressor molecules which induces T cell exhaustion by competitively inhibiting CD28 and dampening the function of HBV-specific T cells. CTLA-4 also plays a role in the regulation of T helper (Th) cell differentiation and influences cytokine release. In addition, CTLA-4 can impact glucose metabolism in hepatocellular carcinoma through its interaction with T regulatory (Treg) cells. This review aims to provide a comprehensive overview of the existing literature related to the role of CTLA-4 in HBV patients across different subsets of T cells. Additionally, we propose a discussion on the possible mechanisms through which CTLA-4 may contribute to HBV infection, as well as the development of HBV-induced cirrhosis and hepatocellular carcinoma.
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Antígeno CTLA-4 , Carcinoma Hepatocelular , Virus de la Hepatitis B , Hepatitis B Crónica , Humanos , Antígeno CTLA-4/metabolismo , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/complicaciones , Virus de la Hepatitis B/inmunología , Virus de la Hepatitis B/fisiología , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/virología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/virología , Linfocitos T Reguladores/inmunología , Cirrosis Hepática/inmunología , Cirrosis Hepática/virologíaRESUMEN
INTRODUCTION: Asthma has been attributed to Th1/Th2 imbalance and inappropriate Th2 responses to environmental allergens. MicroRNAs (miRNAs), 21 to 23 RNA molecules, are first found in mammals and have been implicated in various biological activities. Our previous study found that miR-410 effectively ameliorates airway inflammation in the ovalbumin (OVA)-induced asthma murine model. However, the role of miR-410 in regulating helper T (Th) cell differentiation is not clear. In the present study, we aimed to explore the regulatory effects of miR-410 on the differentiation of Th cells through both in vivo and in vitro studies. METHODS: Dual-luciferase reporter assay was used to find if miR-410 has any direct binding position with VEGF mRNAs. PBMC and CD4+ T cells were isolated and stimulated with OVA. The miR-410 mimics and inhibitors were transfected into CD4+ T cells. The differentiation of Th cells was evaluated by enzyme-linked immunosorbent assay (ELISA) for the concentration of IL-4, IFN-γ, and TGF-ß levels in supernatants. Western Blot was used to detect protein expression and phosphorylation of PI3K and AKT. BALB/c mice were kept in a specific pathogen-free condition and received sterile OVA-free food and water. OVA-induced asthmatic mice model was established. ELISA was used to measure the bronchoalveolar lavage fluid (BALF) concentrations of IL-4, IFN-γ, TGF-ß, and VEGF. Hematoxylin and eosin staining and immunohistochemical staining were conducted to analyze inflammatory cell infiltration, pathological changes, and the expression of VEGF. RESULTS: Dual-luciferase reporter assay showed that miR-410 has no direct binding position with VEGF mRNAs. In the OVA-primed mononuclear cells compared to normal cells, IFN-γ and TGF-ß were decreased while IL-4 and VEGF were increased. This change was reversed while miRNA-410 mimics were transfected into CD4+ T cells. Besides, the OVA-primed CD4+ T cells treated with miR-410 decrease the proliferation of cytokine of Th2 cells as well as phosphorylation of PI3K, and AKT. In OVA-induced asthma mice, IFN-γ and TGF-ß were decreased in BALF while the IL-4 and VEGF were increased. OVA-induced mice with asthma treated with miR-410 mimics showed marked reductions in the infiltration of inflammatory cells as well as IL-4 and VEGF in BALF. The immunohistochemical staining of the expression of VEGF also decreased in OVA-induced asthma mice with the instillation of miR-410. CONCLUSIONS: In this study, we revealed that miR-410 could regulate the differentiation of Th cells via the PI3K-AKT-VEGF signaling pathway in asthma.
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Asma , MicroARNs , Animales , Ratones , Asma/metabolismo , Líquido del Lavado Bronquioalveolar , Diferenciación Celular , Modelos Animales de Enfermedad , Interleucina-4 , Leucocitos Mononucleares , Luciferasas/metabolismo , Pulmón/patología , Mamíferos/genética , Mamíferos/metabolismo , Ratones Endogámicos BALB C , MicroARNs/genética , Ovalbúmina/efectos adversos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta , Factor A de Crecimiento Endotelial Vascular/efectos adversosRESUMEN
BACKGROUND: Our previous study indicated that Hcy exacerbated DSS-induced colitis by facilitating the differentiation of intestinal T helper cell 17 (Th17), but the precise mechanism remains unidentified. Therefore, our current research aims to elucidate the signaling pathway through which Hcy promotes the differentiation of Th17 cells. METHODS: BALb/c mice were randomly assigned into six groups. The model of mice colitis was induced using 3% DSS, while the model of Hyperhomocysteinemia was induced using 1.7% methionine. The concentrations of Hcy and prostaglandin E2 (PGE2) were measured using enzyme-linked immunosorbent assay (ELISA). The protein expressions of cytosolic phospholipase A2 (cPLA2), phosphorylated-cPLA2 (p-cPLA2), cyclooxygenase 2 (COX2), cyclic adenosine monophosphate (cAMP), signal transducer and activator of transcription 3 (STAT3), phosphorylated-STAT3 (p-STAT3), interleukin-17A (IL-17A), and retinoid-related orphan nuclear receptor-γt (RORγt) were assessed using western blot analysis. RESULTS: Compared to the DSS + HHcy group, the addition of the COX inhibitor did not significantly alter the protein expression of p-PLA2/PLA2, but led to significant decreases in serum PGE2 concentration, cAMP, and p-STAT3/STAT3 protein expression. The protein expressions of p-PLA2/PLA2, COX2, and cAMP upstream of STAT3 inhibitor addition did not exhibit significant changes. However, PGE2 concentration and p-STAT3/STAT3 protein expression were notably reduced. After the COX inhibitor and STAT3 inhibitor added, the protein expression of IL-17A and RORγt and the levels of IL-17A and IL-23R in CD4+ T cells were significantly reduced. CONCLUSION: HHcy aggravated DSS-induced colitis by promoting the differentiation and proliferation of Th17 cells through the PGE2 / STAT3 signaling pathway.
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AIM: In this study, we investigated how splenectomy affects natural killer (NK) cell levels in patients with ß-thalassemia major (ß-TM). MATERIALS AND METHODS: Seventy patients with ß-TM (38 splenectomized and 32 nonsplenectomized) and 25 healthy controls were included in this study. The hemogram parameters, ferritin, T lymphocyte, T-helper cell, T-suppressor cell, and NK cell numbers, were measured. RESULTS: The T lymphocyte (CD3+) level was found to be significantly higher in the patient group (p < 0.05). CD3+/CD4+ T lymphocytes were detected to be significantly higher in the patient group (p < 0.05). Although the CD3+/CD4+ T lymphocyte level was significantly higher in the nonsplenectomy group (p < 0.05), this was not the case in the splenectomy group. When the patient and control groups were compared, no significant difference was detected regarding CD3+/CD8+ T lymphocyte levels. CD3-/CD16+CD56+ NK cell level was found to be significantly lower only in the splenectomy group than in the control group (p < 0.05). We found that there was a significant negative correlation between serum ferritin levels and both total lymphocyte (r = -0.617) and CD3+ lymphocyte (r = -0.718) levels in the control group (p < 0.05). A significant negative correlation was detected between serum ferritin levels and CD3-/CD16+CD56+ NK cell levels in the patient group (r = -0.410) (p < 0.05). CONCLUSION: Splenectomy reduces NK cell levels in patients with ß-TM. The negative relationship between ferritin levels and NK cells indicates that ferritin levels should be kept under control in patients with ß-TM.
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Células Asesinas Naturales , Esplenectomía , Talasemia beta , Humanos , Talasemia beta/sangre , Talasemia beta/cirugía , Talasemia beta/inmunología , Células Asesinas Naturales/inmunología , Masculino , Femenino , Adulto , Estudios de Casos y Controles , Adolescente , Adulto Joven , Niño , Ferritinas/sangre , Recuento de LinfocitosRESUMEN
Opisthorchis viverrini infection is endemic in the lower Mekong subregion. The liver is an organ that worms are drawn to and cause damage. However, the immune-related susceptibility in the liver is poorly understood. In this study, we investigated T helper (Th) cell responses in the liver of BALB/c mice and golden Syrian hamsters during 2-28 days post-infection (DPI). We found that Th cell responses were distinct between mice and hamsters in terms of dynamics and polarization. Mice exhibited the early induction of Th1, Th2, Th17, and regulatory T (Treg) cells responses after the presence of O. viverrini worms at 2 DPI. In hamsters, the late induction of Th1/Th17, downregulation of Th2/Treg responses and early elevation of suppressive cytokine interleukin (IL)-10 were found together with swift reduction of Th cell numbers. Interestingly, expressions of IL-4 (Th2 functional cytokine) and Foxp3 (Treg lineage) were completely different between mice and hamsters which elevated in mice but suppressed in hamsters. These results suggest that early induction and well-regulation are related to host resistance. In contrast, late induction of Th cell response might allow immature worms to develop in the host. Our findings provide a greater understanding in Th cell response-related susceptibility in O. viverrini infection which would be targeting immunity for the development of immune-based intervention such as vaccine.
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Opistorquiasis , Opisthorchis , Cricetinae , Animales , Ratones , Opistorquiasis/prevención & control , Mesocricetus , Citocinas , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
Zinc is an essential trace element that plays a crucial role in T cell immunity. During T cell activation, zinc is not only structurally important, but zinc signals can also act as a second messenger. This research investigates zinc signals in T cell activation and their function in T helper cell 1 differentiation. For this purpose, peripheral blood mononuclear cells were activated via the T cell receptor-CD3 complex, and via CD28 as a costimulatory signal. Fast and long-term changes in intracellular zinc and calcium were monitored by flow cytometry. Further, interferon (IFN)-γ was analyzed to investigate the differentiation into T helper 1 cells. We show that fast zinc fluxes are induced via CD3. Also, the intracellular zinc concentration dramatically increases 72 h after anti-CD3 and anti-CD28 stimulation, which goes along with the high release of IFN-γ. Interestingly, we found that zinc signals can function as a costimulatory signal for T helper cell 1 differentiation when T cells are activated only via CD3. These results demonstrate the importance of zinc signaling alongside calcium signaling in T cell differentiation.
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Antígenos CD28 , Diferenciación Celular , Interferón gamma , Activación de Linfocitos , Piridinas , Tionas , Zinc , Humanos , Calcio/metabolismo , Antígenos CD28/agonistas , Antígenos CD28/metabolismo , Complejo CD3/metabolismo , Diferenciación Celular/efectos de los fármacos , Interferón gamma/metabolismo , Ionóforos/farmacología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Transducción de Señal/efectos de los fármacos , Linfocitos T/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Células TH1/inmunología , Células TH1/metabolismo , Células TH1/efectos de los fármacos , Zinc/metabolismo , Zinc/farmacología , Piridinas/química , Piridinas/farmacología , Tionas/química , Tionas/farmacologíaRESUMEN
Impaired class switch memory (CSM) B cell formation is the hallmark of common variable immunodeficiency (CVID). Various T cell abnormalities have been observed in CVID patients indicating inadequate T-cell help to B cells. A major setback in understanding its pathogenesis is due to diverse clinical presentation. Therefore, we performed extensive immunological investigation in a cohort of CVID patients with similar clinical findings in order to unravel the T cell dysfunction and its influence on the defective humoral immune response. All recruited CVID patients exhibited B cells in the normal range, but reduced CSM B cells. However, patients showed reduced T cell proliferation, reduced level of serum Interleukin-9 (IL-9) and frequency of IL-9 expressing CD4 (Th-9) cells. IL-9 supplementation along with CD40 engagement was effective in inducing in vitro CSM B cells formation in CVID patients. Thus, IL-9 supplementation has the potential to restore impaired CSM B cell formation in CVID.
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Inmunodeficiencia Variable Común , Interleucina-9 , Humanos , Células B de Memoria , Cambio de Clase de Inmunoglobulina , Linfocitos TRESUMEN
High-mobility group box protein 1 (HMGB1) is a non-histone deoxyribonucleic acid-binding nuclear protein. In physiological state it is involved in gene transctioripn regulation and cell replication, differentiation and maturation. HMGB1 is actively secreted into the extracellular space in the form of intracellular vesicles, upon stimulation of inflammation and infection, by monocytes, macrophages, dendritic cells (DCs), and other immune cells, and can also be passively released by necrotic or injured cells. After binding with the corresponding receptors, HMGB1 can activate the downstream substrate and trigger a series of biological effects. HMGB1 was mainly dependent on toll-like re ceptors (TLR) 2 and 4, and receptors for advanced glycation end products (RAGE) to trigger intracellular signal transduction, and mediate innate and adoptive immune responses. Besides these, studies have reported the participation of TLR3, TLR9, T-cell immunoglobulin mucin (TIM) 3, CD24, anti-N-methyl-D-aspartate receptor (NMDAR) in Th2 inflammatory response, eosinophilic airway inflammation, and airway hyperresponsiveness, mediated by HMGB1 in asthma. Both clinical and experimental studies suggested that HMGB1 was involved in the pathogenesis of asthma probably by regulating the downstream signaling pathways via corresponding receptors. This article reviews the role of HMGB1 in pathogenesis of asthma, and provides a new theoretical basis for the diagnosis and treatment of asthma.
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Asma , Proteína HMGB1 , Humanos , Proteína HMGB1/metabolismo , Regulación de la Expresión Génica , Transducción de Señal , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Inflamación/metabolismoRESUMEN
Pellino-1 plays a crucial role in cellular proliferation and regulates inflammatory processes. This study investigated Pellino-1 expression patterns and their relationship with CD4+ T-cell subsets in psoriasis patients. Group 1 comprised primarily biopsied psoriasis lesions from 378 patients, multiplex-immunostained for Pellino-1, CD4 and representative T helper (Th) cells (T-bet [Th1], GATA3 [Th2], and RORγt [Th17] and regulatory T cell [FoxP3] markers). Ki-67 labeling was evaluated in the epidermis. Group 2 comprised 43 Pellino-1-positive cases immunostained for Pellino-1 in both lesion and non-lesion skin biopsy samples. Five normal skin biopsies served as controls. Among 378 psoriasis cases, 293 (77.5%) were positive for Pellino-1 in the epidermis. Pellino-1-positivity was higher in psoriasis lesions than in non-lesions and normal skin (52.55% vs. 40.43% vs. 3.48%, p < 0.001; H-score, 72.08 vs. 47.55 vs. 4.40, p < 0.001, respectively). Pellino-1-positive cases also had a significantly higher Ki-67 labeling index (p < 0.001). Epidermal Pellino1-positivity was significantly associated with higher RORγt+ (p = 0.001) and FoxP3+ (p < 0.001) CD4+ T cell ratios but not T-bet+ and GATA3+ CD4+ T cell ratios. Among the CD4+ Pellino-1+ T-cell subsets, the CD4+ Pellino-1+ RORγt+ ratio was significantly associated with epidermal Pellinio-1 expression (p < 0.001). Pellino-1 expression is thus increased in psoriasis lesions and associated with increased epidermal proliferation and CD4+ T-cell subset infiltration, especially Th17 cells. This suggests that Pellino-1 could be a therapeutic target that simultaneously regulates psoriasis epidermal proliferation and immune interactions.
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Psoriasis , Células Th17 , Humanos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Antígeno Ki-67/metabolismo , Epidermis/metabolismo , Psoriasis/tratamiento farmacológico , Proliferación Celular , Factores de Transcripción Forkhead/metabolismoRESUMEN
INTRODUCTION: Allergic diseases are mediated by T helper cell type 2 (Th2) cells, which are differentiated by dendritic cells (DCs). Recently, it was reported that cAMP concentration in DCs is important for inducing allergic responses. However, the regulatory function of cAMP in DCs in Th2 immune responses is unclear. It was hypothesized that the regulation of G protein-coupled receptors (GPCRs) to increase cAMP levels in DCs would reduce Th2 immune responses. METHODS: Human DCs from patients with allergic rhinitis (AR) and from healthy controls were subjected to next-generation sequencing (NGS) to identify potential GPCR. To investigate the functions of GPCR agonists, the in vitro co-culture experiment that THP-1 cells were differentiated into DCs and cultured with human CD4+ T-cells and an AR animal in vivo model were used. RESULTS: Among the GPCRs, the beta-2 adrenergic receptor (ADRB2) of allergic DCs was significantly increased by NGS analysis. The expression of ADRB2 was also increased in Der p 1-treated DCs, which was reduced by treatment with the ADRB2 agonist salbutamol. Salbutamol treatment induced cAMP production in THP-1 derived DCs. In an in vitro co-culture experiment, salbutamol-treated DCs reduced the secretion of Th2 cytokine. In an in vivo AR animal experiment, salbutamol-administered mice showed reduced allergic behavior and Th2 cytokine expression in the nasal mucosa. CONCLUSIONS: The regulation of ADRB2 with salbutamol alleviated the allergic response in vitro DC-T cell co-culture and in vivo AR animal models, suggesting that ADRB2 is a therapeutic target for AR and that ADRB2 agonists may be a promising medication for AR.
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Receptores Adrenérgicos beta 2 , Rinitis Alérgica , Humanos , Animales , Ratones , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Células Dendríticas , Células Th2 , Citocinas/metabolismo , Inmunidad , Albuterol/metabolismoRESUMEN
BACKGROUND: Antiviral intervention in hepatitis B virus (HBV)-infected pregnant women can effectively reduce mother-to-child transmission. However, the immunological characteristics of pregnant women with chronic HBV infection and the effects of antiviral intervention during pregnancy on maternal immune response remain unknown. We aimed to investigate these effects by comparing mothers who received antiviral intervention during pregnancy with those who did not. METHODS: Pregnant women positive for hepatitis B surface antigen and hepatitis B e-antigen (HBsAg+ HBeAg+) were enrolled at delivery, including 34 received prophylactic antiviral intervention during pregnancy (AVI mothers) and 15 did not (NAVI mothers). T lymphocyte phenotypes and functions were analysed using flow cytometry. RESULTS: At delivery, maternal regulatory T cell (Treg) frequency in AVI mothers was significantly higher than that in NAVI mothers (P < 0.002), and CD4+ T cells in AVI mothers displayed a decreased ability to secrete IFN-γ (P = 0.005) and IL-21 (P = 0.043), but an increased ability to secrete IL-10 and IL-4 (P = 0.040 and P = 0.036), which represented a higher Treg frequency, enhanced Th2 response and suppressed Th1 response. Treg frequency among AVI mothers was correlated negatively with serum HBsAg and HBeAg levels. After delivery, the ability of CD4+ T cells or CD8+ T cells to secrete IFN-γ or IL-10 was similar and no significant difference in Treg frequency was found between the two groups. CONCLUSIONS: Prophylactic antiviral intervention during pregnancy has an effect on T cell immunity in pregnant women, which was characterised by increased maternal Treg frequency, enhanced Th2 response and suppressed Th1 response at delivery.
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Hepatitis B , Complicaciones Infecciosas del Embarazo , Femenino , Embarazo , Humanos , Virus de la Hepatitis B , Antígenos de Superficie de la Hepatitis B , Antivirales/uso terapéutico , Antígenos e de la Hepatitis B , Interleucina-10/uso terapéutico , Mujeres Embarazadas , Linfocitos T CD8-positivos , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Hepatitis B/prevención & control , ADN ViralRESUMEN
T-cells play a central role in cell-mediated immunity. While activation of T-cells is major histocompatibility-restricted, the Toll-like receptors (TLRs)- a family of proteins that recognize conserved molecular patterns present on the pathogens-are not well-studied for their expression and function in T-cells. As any association of TLR expression profiles with an effector T-cell subset is unknown, we analyze BALB/c mice-derived CD4+ and CD8+ T-cells' TLR expression profiles. We report: CD4+t-bet+ T-cells are frequent in TLR2LowTLR3HighTLR4Low subpopulation, CD4+GATA3+ T-cells are frequent within the cells with intermediate expression of TLR2, TLR3, TLR4 and TLR11, CD4+FoxP3+ T-cells in TLR2HighTLR3High cells whereas CD4+RORγt + T-cells are frequent in TLR2LowTLR3LowTLR4LowTLR11Low cells. CD4+ effector T-cell subsets may therefore show association with TLRs- TLR3, in particular-expression. In Leishmania donovani infection in BALB/c mice, TLR3 expression on both CD4+ and CD8+ T-cells is reduced. Poly-I:C, a TLR3 ligand, do not have any distinctive effects on the CD4+ effector T-cell subsets. These data suggest that TLRs on T-cells may not function as a primary receptor that controls T-cell function but their distinctive expression profiles on different T-cell subsets suggest plausible immunomodulatory role.