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1.
Medicine (Baltimore) ; 98(41): e17525, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593126

RESUMO

To assess the intra-individual and inter-individuals biological variation and the effect of aging on lymphocyte T-cells subsets.We assessed lymphocyte phenotypes (CD3, CD4, and CD8 T-cells) in 89 HIV-1-infected and 88 uninfected white non-Hispanic men every 6 months, to examine the biological variation for those measurements, and the average change in lymphocyte phenotype over 34 years.The markers showed significant intra-individuality in HIV-infected and uninfected individuals with index of individuality of <1.4. No mean changes were seen over the 34 years, with the exception of percentage CD4T-cells in HIV-uninfected individuals.In the pre-HAART era, HIV-infected individuals experienced an increase in mean absolute CD3 T-cell numbers (11.21 cells/µL, P = 0.02) and absolute CD8 T-cell numbers (34.57 cell/µl, P < .001), and in the percentage of CD8 T-cells (1.45%, P < .001) per year and a significant decrease in mean absolute CD4 T-cell numbers (23.68 cells/µl, P < .001) and in the percentage of CD4 T-cells (1.49%, P < .001) per year.In the post-HAART era, no changes in mean levels were observed in absolute CD3 T-cell count (P = .15) or percentage (P = .99). Significant decreases were seen in mean count (8.56 cells/µl, P < .001) and percentage (0.59%, P < .001) of CD8 T-cells, and increases in mean absolute count (10.72 cells/µl, P < .001) and percentage (0.47%, P < .001) of CD4 T-cells.With the exception of CD4 (%), no average changes per year were seen in lymphocyte phenotype of HIV-uninfected men. The results of coefficients of variation of intra and inter-individuals of this study can be useful for HIV-1 infection monitoring and in addition the observation could be a useful guide for intra- and inter-individual coefficient variations, and establishing quality goal studies of different blood biomarkers in healthy and other diseases.


Assuntos
Síndrome de Imunodeficiência Adquirida/imunologia , Variação Biológica da População/imunologia , Infecções por HIV/imunologia , Subpopulações de Linfócitos T/imunologia , Síndrome de Imunodeficiência Adquirida/etnologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Antirretroviral de Alta Atividade/estatística & dados numéricos , Variação Biológica da População/etnologia , Biomarcadores/sangue , Complexo CD3/efeitos dos fármacos , Complexo CD3/imunologia , Complexo CD3/metabolismo , Antígenos CD4/imunologia , Antígenos CD4/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Senescência Celular/imunologia , Estudos de Coortes , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Humanos , Los Angeles/epidemiologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Fenótipo , Subpopulações de Linfócitos T/metabolismo
2.
Anticancer Res ; 39(9): 4643-4652, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519562

RESUMO

BACKGROUND/AIM: Adenoviral-mediated expression of CD40 ligand (CD40L) on dendritic cells (DCs) activates immune check point CD40/CD40L, enhancing the immunostimulation of DCs and effector cells against human renal carcinoma cells (RCC) and inducing tumor cell apoptosis in vitro. MATERIALS AND METHODS: DCs, isolated from buffy coats from healthy donors, were transduced with adenoviruses carrying human CD40L (Ad-hCD40L). Subsequently maturation marker and cytokine expression were analyzed by fluorescence-activated cell sorting and enzyme-linked immunosorbent assay. RESULTS: Adenoviral transduction induced high expression of soluble CD40L and membrane-bound CD40L, leading to a strong CD40-CD40L interaction in DCs. Interestingly, a T-helper cell type 1 shift of expressed cytokines/chemokines was observed due to the expression of membrane-bound CD40L rather than due to soIuble CD40L alone, which significantly reduced immunoactivation of DCs. However, supernatants of Ad-hCD40L-transduced DCs induced apoptosis of RCC cells. Co-culture of Ad-hCD40L DCs with cytokine-induced killer cells led to a significant stimulation of tumor-specific cytokine-induced killer cells, with increased proliferation and cytotoxicity. CONCLUSION: Use of Ad-hCD40L-transduced DCs is a promising approach to treating RCC.


Assuntos
Antígenos CD40/metabolismo , Ligante de CD40/metabolismo , Carcinoma de Células Renais/metabolismo , Células Dendríticas/metabolismo , Imunomodulação , Neoplasias Renais/metabolismo , Adenoviridae/genética , Biomarcadores , Ligante de CD40/genética , Carcinoma de Células Renais/imunologia , Linhagem Celular Tumoral , Citocinas/metabolismo , Citotoxicidade Imunológica , Células Dendríticas/imunologia , Vetores Genéticos/genética , Humanos , Imunofenotipagem , Neoplasias Renais/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Transdução Genética
3.
Vet Immunol Immunopathol ; 216: 109919, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31446207

RESUMO

Mucosal surfaces such as the gastrointestinal tract, and skin are the front line of host defence and immunity against many pathogens. Gamma delta (γδ) T lymphocytes preferentially localize to the mucosal surfaces in several species including cattle, and are thought to play crucial roles in immunosurveillance and host defence, particularly against mycobacteria. Many γδ T cells are present in young calves, which is the period when calves are thought to be initially exposed to Mycobacterium avium subspecies paratuberculosis (Map). The role of mucosal γδ T cells in cattle, especially during host-pathogen interactions during early pre-clinical phases of infectious disease remains unclear. The purposes of this study were to investigate and characterize WC1+ and WC1neg γδ  T cell subsets in various segments of the gastrointestinal (GI) tract of young calves, and then to examine γδ  T cell subsets in the distal small intestine of calves after experimental intestinal Map infection by direct Peyer's patch inoculation. We show that in healthy calves, the relative proportion of γδ T cells is constant throughout the GI mucosa, though the ileum has significantly more γδ T cells. In the distal intestine, γδ T cells are mainly WC1neg and primarily located within the lamina propria of the jejunum and ileum. In Map-infected intestine, there are higher numbers of γδ T cells in the lamina propria and a greater proportion of WC1+ cells within the epithelial layer compared to control calves. While WC1neg γδ T cells preferentially localize to the distal small intestine of healthy calves, WC1+ γδ T cells are increased in the intestinal mucosa during Map infection, which is suggestive of effector cell function. Further, spectral microscopy and flow cytometry in tandem will lead to improved understanding of the functions of these cells during health and disease.


Assuntos
Doenças dos Bovinos/imunologia , Mucosa Intestinal/metabolismo , Glicoproteínas de Membrana/metabolismo , Mycobacterium avium subsp. paratuberculosis , Paratuberculose/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Bovinos , Sobrevivência Celular , Células Cultivadas , Regulação da Expressão Gênica/imunologia , Mucosa Intestinal/patologia , Glicoproteínas de Membrana/genética , Paratuberculose/metabolismo
4.
Mol Immunol ; 112: 387-393, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31288148

RESUMO

Programmed cell death 4 (Pdcd4) was found to be related to apoptosis upon first discovery. It was later found to play the role of tumor suppressor gene in a variety of tumors by inhibiting transcription and translation. Recently, it has been proposed that it may play an important role in some inflammatory diseases and in the immune response. In our previous study, deficiency of Pdcd4 was found to attenuate the formation of atherosclerotic plaques. This might be because deficiency of Pdcd4 may increase IL-10 expression and lipoautophagy by macrophages and attenuate the formation of foam cells. However, the effect of Pdcd4 on the subsets of T cells in hyperlipidemic mice still remained unclear. In the present study, results showed that Pdcd4 deficiency decreased the percentage of CD8+ T cells and increased that of regulatory T cells (Tregs) under hyperlipidemic conditions both in vitro and in vivo, which may be due to the reduced expression of co-stimulatory molecules CD28 and CD137, and the enhancive expression of co-inhibitory molecules CTLA-4. These results indicated that endogenous Pdcd4 promotes immune response mediated by T cells through regulation of the co-stimulatory molecules expression, which may contribute to the development of advanced atherosclerotic plaques. The current work provides new data to understand the role of Pdcd4 in different T cell subsets under hyperlipidemic microenvironment.


Assuntos
Proteínas Reguladoras de Apoptose/deficiência , Proteínas Reguladoras de Apoptose/metabolismo , Hiperlipidemias/metabolismo , Proteínas de Ligação a RNA/metabolismo , Subpopulações de Linfócitos T/metabolismo , Animais , Apoptose/fisiologia , Antígenos CD28/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Células Espumosas/metabolismo , Interleucina-10/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Placa Aterosclerótica/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
5.
Molecules ; 24(12)2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31212848

RESUMO

BACKGROUND: In mice, postnatal immune development has previously been investigated, and evidence of a delayed maturation of the adaptive immune response has been detected. METHODS: In this study, the effects of red grape polyphenol oral administration on the murine immune response were explored using pregnant mice (TAG/F3 transgenic and wild type (wt) mice) as the animal model. The study was performed during pregnancy as well as during lactation until postnatal day 8. Suckling pups from polyphenol-administered dams as well as day 30 post-weaning pups (dietary-administered with polyphenols) were used. Polyphenol effects were evaluated, measuring splenic cytokine secretion. RESULTS: Phorbol myristate acetate-activated splenocytes underwent the highest cytokine production at day 30 in both wt and TAG/F3 mice. In the latter, release of interferon (IFN)-γ and tumor necrosis factor (TNF)-α was found to be higher than in the wt counterpart. In this context, polyphenols exerted modulating activities on day 30 TAG/F3 mice, inducing release of interleukin (IL)-10 in hetero mice while abrogating release of IL-2, IFN-γ, TNF-α, IL-6, and IL-4 in homo and hetero mice. CONCLUSION: Polyphenols are able to prevent the development of an inflammatory/allergic profile in postnatal TAG/F3 mice.


Assuntos
Contactina 1/genética , Citocinas/metabolismo , Expressão Gênica , Polifenóis/farmacologia , Baço/efeitos dos fármacos , Baço/metabolismo , Desmame , Animais , Animais Recém-Nascidos , Camundongos , Camundongos Transgênicos , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
6.
Int J Mol Sci ; 20(12)2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216735

RESUMO

Bronchial asthma is a chronic disease characterized by reversible airway obstruction, mucus production, and bronchial hyperresponsiveness (BHR). Although Th2 cell-mediated eosinophilic inflammation is an important disease mechanism in the majority of patients with bronchial asthma, recent studies suggest the possible development of Th2-independent airway inflammation and BHR. These non-Th2 endotype patients seem to consist of multiple subgroups, and often do not respond to inhaled corticosteroids. Therefore, to understand the pathogenesis of asthma, it is important to characterize these non-Th2 subgroups. Recently, we demonstrated that Th9 cells induce eosinophil infiltration and eosinophil-independent BHR, and Th9 cells-mediated BHR may be resistant to glucocorticoid. In this review, we summarize the contribution of several T cell subsets in the development of bronchial asthma and introduce our recent study demonstrating Th9 cell-mediated and eosinophil-independent BHR.


Assuntos
Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/metabolismo , Eosinófilos/imunologia , Eosinófilos/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Asma/tratamento farmacológico , Asma/imunologia , Asma/metabolismo , Hiper-Reatividade Brônquica/tratamento farmacológico , Humanos , Subpopulações de Linfócitos T/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo
7.
Int J Mol Sci ; 20(11)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31159348

RESUMO

During the last few years, the gut microbiota has gained increasing attention as a consequence of its emerging role as a modulator of the immune system. With the advent of the era of checkpoint inhibitors immunotherapy and adoptive cell transfer (ACT) in oncology, these findings became of primary relevance in light of experimental data that suggested the microbiota involvement as a plausible predictor of a good or poor response. These remarks justify the efforts to pinpoint the specific actions of the microbiota and to identify new strategies to favorably edit its composition.


Assuntos
Imunoterapia , Microbiota , Neoplasias/etiologia , Neoplasias/terapia , Animais , Biomarcadores Tumorais , Microbioma Gastrointestinal/imunologia , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Imunoterapia Adotiva , Microbiota/imunologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo
8.
BMC Cancer ; 19(1): 531, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151416

RESUMO

BACKGROUND: Molecular markers predicting survival in esophageal adenocarcinoma (EAC) are rare. Specifically, in favorable oncologic situations, e.g. nodal negativity or major neoadjuvant therapy response, there is a lack of additional risk factors that serve to predict patients' outcome more precisely. This study evaluated X-linked inhibitor of apoptosis protein (XIAP) as a potential marker improving outcome prediction. METHODS: Tissue microarrays from 362 patients that were diagnosed with resectable EAC were included in the study. XIAP was stained by immunohistochemistry and correlated to clinical outcome, molecular markers and markers of the cellular tumor microenvironment. RESULTS: XIAP did not impact on overall survival (OS) in the whole study collective. Subgroup analyses stratifying for common genetic markers (TP53, ERBB2, ARID1A/SWI/SNF) did not disclose any impact of XIAP expression on survival. Detailed subgroup analyses of [1] nodal negative patients, [2] highly T-cell infiltrated tumors and [3] therapy responders to neoadjuvant treatment revealed a significant inverse role of high XIAP expression in these specific oncologic situations; elevated XIAP expression detrimentally affected patients' outcome in these subgroups. [1]: OS XIAP low: 202 months (m) vs. XIAP high: 38 m; [2]: OS 116 m vs. 28.2 m; [3]: OS 31 m vs. 4 m). CONCLUSIONS: Our data suggest XIAP expression in EAC as a worthy tool to improve outcome prediction in specific oncologic settings that might directly impact on clinical diagnosis and treatment of EAC in the future.


Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidade , Linfócitos do Interstício Tumoral/metabolismo , Terapia Neoadjuvante , Subpopulações de Linfócitos T/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Esofagectomia , Feminino , Humanos , Imuno-Histoquímica , Linfonodos/patologia , Masculino , Terapia Neoadjuvante/métodos , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
9.
Int J Mol Sci ; 20(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083348

RESUMO

Detrimental health consequences from exposure to space radiation are a major concern for long-duration human exploration missions to the Moon or Mars. Cellular responses to radiation are expected to be heterogeneous for space radiation exposure, where only high-energy protons and other particles traverse a fraction of the cells. Therefore, assessing DNA damage and DNA damage response in individual cells is crucial in understanding the mechanisms by which cells respond to different particle types and energies in space. In this project, we identified a cell-specific signature for radiation response by using single-cell transcriptomics of human lymphocyte subpopulations. We investigated gene expression in individual human T lymphocytes 3 h after ex vivo exposure to 2-Gy gamma rays while using the single-cell sequencing technique (10X Genomics). In the process, RNA was isolated from ~700 irradiated and ~700 non-irradiated control cells, and then sequenced with ~50 k reads/cell. RNA in each of the cells was distinctively barcoded prior to extraction to allow for quantification for individual cells. Principal component and clustering analysis of the unique molecular identifier (UMI) counts classified the cells into three groups or sub-types, which correspond to CD4+, naïve, and CD8+/NK cells. Gene expression changes after radiation exposure were evaluated using negative binomial regression. On average, BBC3, PCNA, and other TP53 related genes that are known to respond to radiation in human T cells showed increased activation. While most of the TP53 responsive genes were upregulated in all groups of cells, the expressions of IRF1, STAT1, and BATF were only upregulated in the CD4+ and naïve groups, but were unchanged in the CD8+/NK group, which suggests that the interferon-gamma pathway does not respond to radiation in CD8+/NK cells. Thus, single-cell RNA sequencing technique was useful for simultaneously identifying the expression of a set of genes in individual cells and T lymphocyte subpopulation after gamma radiation exposure. The degree of dependence of UMI counts between pairs of upregulated genes was also evaluated to construct a similarity matrix for cluster analysis. The cluster analysis identified a group of TP53-responsive genes and a group of genes that are involved in the interferon gamma pathway, which demonstrate the potential of this method for identifying previously unknown groups of genes with similar expression patterns.


Assuntos
Exposição à Radiação , Fator de Transcrição STAT1/metabolismo , Análise de Sequência de RNA , Transdução de Sinais , Análise de Célula Única , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/efeitos da radiação , Proteína Supressora de Tumor p53/metabolismo , Análise por Conglomerados , Raios gama , Humanos , Imunofenotipagem , Reprodutibilidade dos Testes , Transdução de Sinais/genética , Transdução de Sinais/efeitos da radiação , Regulação para Cima/genética , Regulação para Cima/efeitos da radiação
10.
EBioMedicine ; 43: 424-434, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31085101

RESUMO

BACKGROUND: The delivery of therapeutic proteins to selected sites within the central nervous system (CNS) parenchyma is a major challenge in the treatment of various neurodegenerative disorders. As brain-derived neurotrophic factor (BDNF) is reduced in the brain of people with Alzheimer's disease (AD) and its administration has shown promising therapeutic effects in mouse model of the disease, we generated a novel platform for T cell-based BDNF delivery into the brain parenchyma. METHODS: We generated amyloid beta-protein (Aß)-specific CD4 T cells (Aß-T cells), genetically engineered to express BDNF, and injected them intracerebroventricularly into the 5XFAD mouse model of AD. FINDINGS: The BDNF-secreting Aß-T cells migrated efficiently to amyloid plaques, where they significantly increased the levels of BDNF, its receptor TrkB, and various synaptic proteins known to be reduced in AD. Furthermore, the injected mice demonstrated reduced levels of beta-secretase 1 (BACE1)-a protease essential in the cleavage process of the amyloid precursor protein-and ameliorated amyloid pathology and inflammation within the brain parenchyma. INTERPRETATION: A T cell-based delivery of proteins into the brain can serve as a platform to modulate neurotoxic inflammation and to promote neuronal repair in neurodegenerative diseases.


Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/imunologia , Peptídeos beta-Amiloides/metabolismo , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Animais , Biomarcadores , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/genética , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Epitopos de Linfócito T/imunologia , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Transgênicos , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Células Piramidais/imunologia , Células Piramidais/metabolismo , Células Piramidais/patologia , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
12.
Nat Immunol ; 20(6): 747-755, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31061531

RESUMO

Despite gathering evidence that ubiquitylation can direct non-degradative outcomes, most investigations of ubiquitylation in T cells have focused on degradation. Here, we integrated proteomic and transcriptomic datasets from primary mouse CD4+ T cells to establish a framework for predicting degradative or non-degradative outcomes of ubiquitylation. Di-glycine remnant profiling was used to reveal ubiquitylated proteins, which in combination with whole-cell proteomic and transcriptomic data allowed prediction of protein degradation. Analysis of ubiquitylated proteins identified by di-glycine remnant profiling indicated that activation of CD4+ T cells led to an increase in non-degradative ubiquitylation. This correlated with an increase in non-proteasome-targeted K29, K33 and K63 polyubiquitin chains. This study revealed over 1,200 proteins that were ubiquitylated in primary mouse CD4+ T cells and highlighted the relevance of non-proteasomally targeted ubiquitin chains in T cell signaling.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Ativação Linfocitária/imunologia , Proteoma , Proteômica , Animais , Perfilação da Expressão Gênica , Ativação Linfocitária/genética , Espectrometria de Massas , Camundongos , Poliubiquitina/metabolismo , Proteômica/métodos , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Transcriptoma , Ubiquitinação
13.
Nat Immunol ; 20(7): 928-942, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31061532

RESUMO

To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)+HLA-DRAhi sublining fibroblasts, IL1B+ pro-inflammatory monocytes, ITGAX+TBX21+ autoimmune-associated B cells and PDCD1+ peripheral helper T (TPH) cells and follicular helper T (TFH) cells. We defined distinct subsets of CD8+ T cells characterized by GZMK+, GZMB+, and GNLY+ phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1+HLA-DRAhi fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Perfilação da Expressão Gênica , Membrana Sinovial/metabolismo , Transcriptoma , Artrite Reumatoide/patologia , Autoimunidade/genética , Biomarcadores , Biologia Computacional/métodos , Estudos Transversais , Citocinas/metabolismo , Fibroblastos/metabolismo , Citometria de Fluxo , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Leucócitos/imunologia , Leucócitos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Transdução de Sinais , Análise de Célula Única/métodos , Membrana Sinovial/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Fluxo de Trabalho
14.
EBioMedicine ; 43: 411-423, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31053557

RESUMO

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory disease and a leading cause of progressive neurological disability among young adults. DNA methylation, which intersects genes and environment to control cellular functions on a molecular level, may provide insights into MS pathogenesis. METHODS: We measured DNA methylation in CD4+ T cells (n = 31), CD8+ T cells (n = 28), CD14+ monocytes (n = 35) and CD19+ B cells (n = 27) from relapsing-remitting (RRMS), secondary progressive (SPMS) patients and healthy controls (HC) using Infinium HumanMethylation450 arrays. Monocyte (n = 25) and whole blood (n = 275) cohorts were used for validations. FINDINGS: B cells from MS patients displayed most significant differentially methylated positions (DMPs), followed by monocytes, while only few DMPs were detected in T cells. We implemented a non-parametric combination framework (omicsNPC) to increase discovery power by combining evidence from all four cell types. Identified shared DMPs co-localized at MS risk loci and clustered into distinct groups. Functional exploration of changes discriminating RRMS and SPMS from HC implicated lymphocyte signaling, T cell activation and migration. SPMS-specific changes, on the other hand, implicated myeloid cell functions and metabolism. Interestingly, neuronal and neurodegenerative genes and pathways were also specifically enriched in the SPMS cluster. INTERPRETATION: We utilized a statistical framework (omicsNPC) that combines multiple layers of evidence to identify DNA methylation changes that provide new insights into MS pathogenesis in general, and disease progression, in particular. FUND: This work was supported by the Swedish Research Council, Stockholm County Council, AstraZeneca, European Research Council, Karolinska Institutet and Margaretha af Ugglas Foundation.


Assuntos
Metilação de DNA , Imunidade , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Transdução de Sinais , Adulto , Idoso , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Biomarcadores , Ilhas de CpG , Progressão da Doença , Suscetibilidade a Doenças , Feminino , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Crônica Progressiva/etiologia , Esclerose Múltipla Crônica Progressiva/metabolismo , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/etiologia , Esclerose Múltipla Recidivante-Remitente/metabolismo , Locos de Características Quantitativas , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
15.
Nat Commun ; 10(1): 2352, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138793

RESUMO

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.


Assuntos
Proteína 10 de Linfoma CCL de Células B/imunologia , Proteínas Adaptadoras de Sinalização CARD/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Proteína 10 de Linfoma CCL de Células B/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Diferenciação Celular , Citocinas/imunologia , Melanoma Experimental , Camundongos , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , NF-kappa B/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo
17.
Immunity ; 50(6): 1498-1512.e5, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31097342

RESUMO

Despite compelling rates of durable clinical responses to programmed cell death-1 (PD-1) blockade, advances are needed to extend these benefits to resistant tumors. We found that tumor-bearing mice deficient in the chemokine receptor CXCR3 responded poorly to anti-PD-1 treatment. CXCR3 and its ligand CXCL9 were critical for a productive CD8+ T cell response in tumor-bearing mice treated with anti-PD-1 but were not required for the infiltration of CD8+ T cells into tumors. The anti-PD-1-induced anti-tumor response was facilitated by CXCL9 production from intratumoral CD103+ dendritic cells, suggesting that CXCR3 facilitates dendritic cell-T cell interactions within the tumor microenvironment. CXCR3 ligands in murine tumors and in plasma of melanoma patients were an indicator of clinical response to anti-PD-1, and their induction in non-responsive murine tumors promoted responsiveness to anti-PD-1. Our data suggest that the CXCR3 chemokine system is a biomarker for sensitivity to PD-1 blockade and that augmenting the intratumoral function of this chemokine system could improve clinical outcomes.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Imunomodulação/efeitos dos fármacos , Neoplasias/imunologia , Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Receptores CXCR3/metabolismo , Animais , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Modelos Animais de Doenças , Epigênese Genética , Humanos , Ativação Linfocitária , Camundongos , Camundongos Knockout , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Am Soc Clin Oncol Educ Book ; 39: 165-174, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31099649

RESUMO

Emerging immunotherapeutic approaches have revolutionized the treatment of multiple malignancies. Immune checkpoint blockers (ICBs) have enabled never-before-seen success rates in durable tumor control and enhanced survival benefit in patients with advanced cancers. However, this effect is not universal, resulting in responder and nonresponder populations not only between, but also within solid tumor types. Although ICBs are thought to be most effective against tumors with more genetic mutations and higher antigen loads, this is not always the case for all cancers or for all patients within a cancer subtype. Furthermore, debilitating and sometimes deadly immune-related adverse events (irAEs) have resulted from aberrant activation of T-cell responses following immunotherapy. Thus, we must identify new ways to overcome resistance to ICB-based immunotherapies and limit irAEs. In fact, preclinical and clinical data have identified abnormalities in the tumor microenvironment (TME) that can thwart the efficacy of immunotherapies such as ICBs. Here, we will discuss how reprogramming various facets of the TME (blood vessels, myeloid cells, and regulatory T cells [Tregs]) may overcome TME-instigated resistance mechanisms to immunotherapy. We will discuss clinical applications of this strategic approach, including the recent successful phase III trial combining bevacizumab with atezolizumab and chemotherapy for metastatic nonsquamous non-small cell lung cancer that led to rapid approval by the U.S. Food and Drug Administration of this regimen for first-line treatment. Given the accelerated testing and approval of ICBs combined with various targeted therapies in larger numbers of patients with cancer, we will discuss how these concepts and approaches can be incorporated into clinical practice to improve immunotherapy outcomes.


Assuntos
Reprogramação Celular/genética , Reprogramação Celular/imunologia , Neoplasias/etiologia , Neoplasias/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Terapia Combinada , Progressão da Doença , Humanos , Imunomodulação , Imunoterapia , Terapia de Alvo Molecular , Células Mieloides/imunologia , Células Mieloides/metabolismo , Neoplasias/terapia , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Resultado do Tratamento
19.
Scand J Immunol ; 90(3): e12794, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31141185

RESUMO

Natural killer T (NKT) cells are αß T cell receptor (TCR) expressing innate-like T cells that display natural killer (NK) cell markers. Based on TCR characteristics, they are divided into two groups restricted to the MHC class I-like molecule CD1d. Type I NKT cells, most extensively studied, are identified by a semi-invariant Vα14-Jα18 (mouse, Vα24-Jα18 in humans) TCR reactive to the prototypic ligand α-galactosylceramide presented on CD1d. In contrast, type II NKT cells display diverse TCR reacting to different CD1d-presented ligands. There are no reagents that identify all type II NKT cells, limiting their exploration. Here, we searched for novel type II NKT cells by comparing Jα18-/- MHCII-/- mice that harbour type II but not type I NKT cells, and CD1d-/- MHCII-/- mice, lacking all NKT cells. We identified significantly larger populations of CD4+ and CD4- CD8- (double negative, DN) TCRß+ cells expressing NKG2D or NKG2A/C/E in Jα18-/- MHCII-/- mice compared with CD1d-/- MHCII-/- mice, suggesting that 30%-50% of these cells were type II NKT cells. They expressed CD122, NK1.1, CXCR3 and intermediate/low levels of CD45RB. Further, the CD4+ subset was CD69+ , while the DN cells were CD49b+ and CD62L+ . Both subsets expressed the NKT cell-associated promyelocytic leukaemia zinc finger (PLZF) transcription factor and Tbet, while fewer cells expressed RORγt. NKG2D+ CD4+ and DN populations were producers of IFN-γ, but rarely IL-4 and IL-17. Taken together, we identify a novel subset of primary CD4+ and DN type II NKT cells that expresses NKG2 receptors have typical NKT cell phenotypes and a TH1-like cytokine production.


Assuntos
Antígenos CD1d/imunologia , Antígenos CD1d/metabolismo , Biomarcadores/metabolismo , Células Matadoras Naturais/imunologia , Células T Matadoras Naturais/imunologia , Animais , Feminino , Galactosilceramidas/imunologia , Galactosilceramidas/metabolismo , Interferon gama/imunologia , Interferon gama/metabolismo , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Células T Matadoras Naturais/metabolismo , Proteína com Dedos de Zinco da Leucemia Promielocítica/imunologia , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
20.
EBioMedicine ; 43: 587-593, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31056472

RESUMO

BACKGROUND: Autoimmunity and allergy have been associated with decreased number and function of regulatory T-cells (Tregs) and low interleukin-2 (IL-2) levels. We aimed to investigate if the release of IL-2 from peripheral blood mononuclear cells (PBMCs) stimulated with pathogenic airway bacteria was associated with development of allergy-outcomes in early childhood. METHODS: PBMCs were isolated at age 6 months in 331 infants from the Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC2000) mother-child cohort, and subsequently stimulated with H. influenzae, M. catarrhalis and S. pneumoniae in in vitro cultures. Levels of cytokines (IL-2, IL-10, IFN-γ, TNF-α, IL-5, IL-13 and IL-17A) were determined in the supernatant by electrochemiluminescence immunoassays. The immune profiles were analyzed for association with development of total-IgE, allergic sensitization and rhinitis during the first 7 years of life using regression models and principal component analysis (PCA). FINDINGS: An attenuated IL-2 response to stimulation with H. influenzae (p = 0∙011) and M. catarrhalis (p = 0∙027) was associated with elevated total-IgE at age 7, which was confirmed in a multivariate PCA model including all cytokine measurements (PC2, p = 0∙032). An immune profile with both reduced IL-2 and elevated IL-5 was associated with increased risk of allergic rhinitis (PC3, p = 0∙038). We found no associations with development of allergic sensitization. INTERPRETATION: A reduced IL-2 response from PBMCs exposed to common pathogenic airway bacteria at age 6 months was associated with elevated total-IgE and allergic rhinitis during the first 7 years of life. These findings suggest that suppressed Treg activity in early life may herald onset of allergy in early childhood, which could be a target for low-dose IL-2 trials in the future. FUND: COPSAC is funded by private and public research funds all listed on www.copsac.com.


Assuntos
Bactérias/imunologia , Imunoglobulina E/imunologia , Interleucina-2/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Rinite Alérgica/etiologia , Rinite Alérgica/metabolismo , Fatores Etários , Alérgenos/imunologia , Infecções Bacterianas/complicações , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Estudos de Coortes , Citocinas/metabolismo , Suscetibilidade a Doenças , Feminino , Humanos , Imunização , Imunoglobulina E/sangue , Imunofenotipagem , Lactente , Recém-Nascido , Masculino , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
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