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1.
Nat Commun ; 12(1): 1446, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33664261

RESUMO

Invariant natural killer T cells (iNKT cells) differentiate into thymic and peripheral NKT1, NKT2 and NKT17 subsets. Here we use RNA-seq and ATAC-seq analyses and show iNKT subsets are similar, regardless of tissue location. Lung iNKT cell subsets possess the most distinct location-specific features, shared with other innate lymphocytes in the lung, possibly consistent with increased activation. Following antigenic stimulation, iNKT cells undergo chromatin and transcriptional changes delineating two populations: one similar to follicular helper T cells and the other NK or effector like. Phenotypic analysis indicates these changes are observed long-term, suggesting that iNKT cells gene programs are not fixed, but they are capable of chromatin remodeling after antigen to give rise to additional subsets.


Assuntos
Pulmão/citologia , Células T Matadoras Naturais/citologia , Subpopulações de Linfócitos T/citologia , Timo/citologia , Animais , Diferenciação Celular/imunologia , Cromatina/genética , Feminino , Pulmão/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células T Matadoras Naturais/imunologia , Subpopulações de Linfócitos T/imunologia , Timo/imunologia , Transcriptoma/genética
2.
Nucleic Acids Res ; 48(19): 10890-10908, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33021676

RESUMO

Although endogenous retroviruses (ERVs) are known to harbor cis-regulatory elements, their role in modulating cellular immune responses remains poorly understood. Using an RNA-seq approach, we show that several members of the ERV9 lineage, particularly LTR12C elements, are activated upon HIV-1 infection of primary CD4+ T cells. Intriguingly, HIV-1-induced ERVs harboring transcription start sites are primarily found in the vicinity of immunity genes. For example, HIV-1 infection activates LTR12C elements upstream of the interferon-inducible genes GBP2 and GBP5 that encode for broad-spectrum antiviral factors. Reporter assays demonstrated that these LTR12C elements drive gene expression in primary CD4+ T cells. In line with this, HIV-1 infection triggered the expression of a unique GBP2 transcript variant by activating a cryptic transcription start site within LTR12C. Furthermore, stimulation with HIV-1-induced cytokines increased GBP2 and GBP5 expression in human cells, but not in macaque cells that naturally lack the GBP5 gene and the LTR12C element upstream of GBP2. Finally, our findings suggest that GBP2 and GBP5 have already been active against ancient viral pathogens as they suppress the maturation of the extinct retrovirus HERV-K (HML-2). In summary, our findings uncover how human cells can exploit remnants of once-infectious retroviruses to regulate antiviral gene expression.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Retrovirus Endógenos/genética , Regulação da Expressão Gênica/imunologia , Infecções por HIV/genética , Regiões Promotoras Genéticas , Subpopulações de Linfócitos T/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/imunologia , Células HEK293 , Infecções por HIV/imunologia , HIV-1 , Humanos , Macaca mulatta , Subpopulações de Linfócitos T/citologia
3.
Nucleic Acids Res ; 48(18): 10164-10183, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-32990751

RESUMO

T cells are central to the immune response against various pathogens and cancer cells. Complex networks of transcriptional and post-transcriptional regulators, including microRNAs (miRNAs), coordinate the T cell activation process. Available miRNA datasets, however, do not sufficiently dissolve the dynamic changes of miRNA controlled networks upon T cell activation. Here, we established a quantitative and time-resolved expression pattern for the entire miRNome over a period of 24 h upon human T-cell activation. Based on our time-resolved datasets, we identified central miRNAs and specified common miRNA expression profiles. We found the most prominent quantitative expression changes for miR-155-5p with a range from initially 40 molecules/cell to 1600 molecules/cell upon T-cell activation. We established a comprehensive dynamic regulatory network of both the up- and downstream regulation of miR-155. Upstream, we highlight IRF4 and its complexes with SPI1 and BATF as central for the transcriptional regulation of miR-155. Downstream of miR-155-5p, we verified 17 of its target genes by the time-resolved data recorded after T cell activation. Our data provide comprehensive insights into the range of stimulus induced miRNA abundance changes and lay the ground to identify efficient points of intervention for modifying the T cell response.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Ativação Linfocitária , MicroRNAs/metabolismo , Subpopulações de Linfócitos T/metabolismo , Adulto , Linfócitos T CD4-Positivos/citologia , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Subpopulações de Linfócitos T/citologia , Adulto Jovem
4.
PLoS One ; 15(9): e0239695, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32970753

RESUMO

Wuhan, China was the epicenter of the 2019 coronavirus outbreak. As a designated hospital for COVID-19, Wuhan Pulmonary Hospital has received over 700 COVID-19 patients. With the COVID-19 becoming a pandemic all over the world, we aim to share our epidemiological and clinical findings with the global community. We studied 340 confirmed COVID-19 patients with clear clinical outcomes from Wuhan Pulmonary Hospital, including 310 discharged cases and 30 death cases. We analyzed their demographic, epidemiological, clinical and laboratory data and implemented our findings into an interactive, free access web application to evaluate COVID-19 patient's severity level. Our results show that baseline T cell subsets results differed significantly between the discharged cases and the death cases in Mann Whitney U test: Total T cells (p < 0.001), Helper T cells (p <0.001), Suppressor T cells (p <0.001), and TH/TSC (Helper/Suppressor ratio, p<0.001). Multivariate logistic regression model with death or discharge as the outcome resulted in the following significant predictors: age (OR 1.05, 95% CI, 1.00 to 1.10), underlying disease status (OR 3.42, 95% CI, 1.30 to 9.95), Helper T cells on the log scale (OR 0.22, 95% CI, 0.12 to 0.40), and TH/TSC on the log scale (OR 4.80, 95% CI, 2.12 to 11.86). The AUC for the logistic regression model is 0.90 (95% CI, 0.84 to 0.95), suggesting the model has a very good predictive power. Our findings suggest that while age and underlying diseases are known risk factors for poor prognosis, patients with a less damaged immune system at the time of hospitalization had higher chance of recovery. Close monitoring of the T cell subsets might provide valuable information of the patient's condition change during the treatment process. Our web visualization application can be used as a supplementary tool for the evaluation.


Assuntos
Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/mortalidade , Pneumonia Viral/diagnóstico , Pneumonia Viral/mortalidade , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/citologia , Adulto , Idoso , Betacoronavirus , China , Humanos , Internet , Modelos Logísticos , Pessoa de Meia-Idade , Pandemias , Alta do Paciente , Fatores de Risco , Centros de Atenção Terciária
5.
Cell ; 183(4): 968-981.e7, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-32966765

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4-6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. We apply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage. Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C.


Assuntos
Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Síndrome de Resposta Inflamatória Sistêmica/patologia , Autoanticorpos/sangue , Betacoronavirus/isolamento & purificação , Criança , Pré-Escolar , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Feminino , Humanos , Imunidade Humoral , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/imunologia , Síndrome de Linfonodos Mucocutâneos/patologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Análise de Componente Principal , Proteoma/análise , Índice de Gravidade de Doença , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
6.
J Cell Mol Med ; 24(19): 11603-11606, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32864865

RESUMO

A novel pneumonia-associated respiratory syndrome named coronavirus disease-2019 (COVID-19), which was caused by SARS-CoV-2,broke out in Wuhan, China, in the end of 2019. Unfortunately, there is no specific antiviral agent or vaccine available to treat SARS-CoV-2 infections. The information regarding the immunological characteristics in COVID-19 patients remains limited. Here, we collected the blood samples from 18 healthy donors (HD) and 38 COVID-19 patients to analyze changes on γδ T cell population. In comparison with HD, the γδ T cell percentage decreased, while the activation marker CD25 expression increased in response to SARS-CoV-2 infection. Interestingly, the CD4 expression was upregulated in γδ T cells reflecting the occurrence of a specific effector cell population, which may serve as a biomarker for the assessment of SARS-CoV-2 infection.


Assuntos
Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Betacoronavirus/fisiologia , Biomarcadores , Antígenos CD4/metabolismo , China , Citometria de Fluxo , Humanos , Imunidade Inata , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Pandemias , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo
7.
Science ; 369(6503)2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32732394

RESUMO

The lymphoid system is intimately involved in immunological processes. The small lymphocyte that circulates through blood into lymphoid tissues, then through the lymph and back to the blood through the thoracic duct, is able to initiate immune responses after appropriate stimulation by antigen. However, the lymphocytes found in the thymus are deficient in this ability despite the fact that the thymus plays a central role in lymphocyte production and in ensuring the normal development of immunological faculty. During embryogenesis, lymphocytes are present in the thymus before they can be identified in the circulation and in other lymphoid tissues. They become "educated" in the thymus to recognize a great diversity of peptide antigens bound to the body's own marker antigen, the major histocompatibility complex, but they are purged if they strongly react against their own self-components. Lymphocytes differentiate to become various T cell subsets and then exit through the bloodstream to populate certain areas of the lymphoid system as peripheral T lymphocytes with distinct markers and immune functions.


Assuntos
Imunoterapia , Subpopulações de Linfócitos T/imunologia , Timo/imunologia , Animais , Linfócitos B/imunologia , Diferenciação Celular , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Humanos , Linfoma/imunologia , Linfoma/terapia , Camundongos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/terapia , Transplante de Pele , Subpopulações de Linfócitos T/citologia , Timo/citologia
8.
Nat Commun ; 11(1): 2857, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32504069

RESUMO

Virtual memory T (TVM) cells are antigen-naïve CD8+ T cells that exist in a semi-differentiated state and exhibit marked proliferative dysfunction in advanced age. High spare respiratory capacity (SRC) has been proposed as a defining metabolic characteristic of antigen-experienced memory T (TMEM) cells, facilitating rapid functionality and survival. Given the semi-differentiated state of TVM cells and their altered functionality with age, here we investigate TVM cell metabolism and its association with longevity and functionality. Elevated SRC is a feature of TVM, but not TMEM, cells and it increases with age in both subsets. The elevated SRC observed in aged mouse TVM cells and human CD8+ T cells from older individuals is associated with a heightened sensitivity to IL-15. We conclude that elevated SRC is a feature of TVM, but not TMEM, cells, is driven by physiological levels of IL-15, and is not indicative of enhanced functionality in CD8+ T cells.


Assuntos
Envelhecimento/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/ultraestrutura , Diferenciação Celular/imunologia , Proliferação de Células , Modelos Animais de Doenças , Feminino , Humanos , Vírus da Influenza A/imunologia , Influenza Humana/sangue , Influenza Humana/imunologia , Influenza Humana/virologia , Masculino , Camundongos , Microscopia Eletrônica de Transmissão , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/ultraestrutura , Adulto Jovem
9.
PLoS One ; 15(6): e0235174, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574226

RESUMO

AIM: To investigate markers of systemic inflammation in pre- and postmenopausal women and identify possible predictors of systemic inflammation with menopause. METHODS: Cross-sectional study of 69 healthy women between 45- and 60 years. Blood samples were collected to assess leukocyte subsets and plasma cytokines. MRI and DXA scans were performed to assess body composition. Through uni- and multivariate analyses, follicle-stimulating hormone (FSH), visceral fat mass and age were evaluated as predictors of systemic inflammation in relation to menopause. RESULTS: Postmenopausal women tended to have higher leukocyte counts (5.4 x109 vs. 4.9 x109 cells/l, p = 0.05) reflected in increased total lymphocytes (1.8 x109 vs. 1.6 x109 cells/l, p = 0.01) and monocytes (0.5 x109 vs. 0.4 x109 cells/l, p = 0.02), compared to premenopausal women. Increased visceral fat mass was a strong predictor of high leukocyte subsets. Postmenopausal women had higher plasma TNF-α (2.24 vs. 1.91 pg/ml, p = 0.01) and IL-6 (0.45 vs. 0.33 pg/ml, p = 0.004) compared to premenopausal women and high FSH was a significant predictor of increased plasma TNF-α, IL-1ß and IL-6. Menopause was further associated with increased T-cells (1,336 vs. 1,128 cells/µl, p = 0.04) reflected in significantly higher counts of exhausted-, senescent-, and memory CD4+ T-cell subsets. CONCLUSIONS: Menopause is associated with increased systemic inflammation as well as exhausted- and senescent T-cells. We suggest, that both increased visceral fat mass and declining sex hormone levels might contribute to postmenopausal systemic inflammation and calls for further large-scale studies to confirm these findings.


Assuntos
Citocinas/imunologia , Inflamação/imunologia , Pós-Menopausa/imunologia , Subpopulações de Linfócitos T/imunologia , Absorciometria de Fóton/métodos , Composição Corporal , Citocinas/sangue , Citocinas/metabolismo , Feminino , Hormônio Foliculoestimulante/sangue , Hormônio Foliculoestimulante/imunologia , Hormônios Esteroides Gonadais/sangue , Hormônios Esteroides Gonadais/imunologia , Humanos , Inflamação/sangue , Inflamação/metabolismo , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Linfócitos/citologia , Linfócitos/imunologia , Linfócitos/metabolismo , Imagem por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Monócitos/citologia , Monócitos/imunologia , Monócitos/metabolismo , Análise Multivariada , Pós-Menopausa/sangue , Pós-Menopausa/metabolismo , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo
10.
Cytometry A ; 97(8): 772-776, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32542842

RESUMO

A reduced peripheral blood absolute lymphocyte count with an elevated neutrophil count has been a consistent observation in hospitalized coronavirus disease 2019 (COVID-19) patients. In this brief meta-analysis, the reduction of lymphocyte subset counts in COVID-19 patients was investigated across 20 peer-reviewed studies meeting criteria for reporting lymphocyte subset counts and COVID-19 disease severity. CD4+ T cell, CD8+ T cell, B cell, NK cell, and total lymphocyte cell counts all showed statistically significant reduction in patients with severe/critical COVID-19 disease compared to mild/moderate disease. T-cell subsets showed the largest standardized magnitude of change. In some studies, multivariate analysis has shown that CD4 and/or CD8 T-cells counts are independently predictive of patient outcomes. © 2020 International Society for Advancement of Cytometry.


Assuntos
Linfócitos B/citologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Infecções por Coronavirus/sangue , Células Matadoras Naturais/citologia , Pneumonia Viral/sangue , Subpopulações de Linfócitos T/citologia , Betacoronavirus , Humanos , Contagem de Linfócitos , Neutrófilos/citologia , Pandemias
11.
Nat Rev Immunol ; 20(8): 499-506, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32493982

RESUMO

We are just beginning to understand the diversity of the peripheral T cell compartment, which arises from the specialization of different T cell subsets and the plasticity of individual naive T cells to adopt different fates. Although the progeny of a single T cell can differentiate into many phenotypes following infection, individual T cells are biased towards particular phenotypes. These biases are typically ascribed to random factors that occur during and after antigenic stimulation. However, the T cell compartment does not remain static with age, and shifting immune challenges during ontogeny give rise to T cells with distinct functional properties. Here, we argue that the developmental history of naive T cells creates a 'hidden layer' of diversity that persists into adulthood. Insight into this diversity can provide a new perspective on immunity and immunotherapy across the lifespan.


Assuntos
Imunidade Celular/imunologia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Animais , Diferenciação Celular/imunologia , Humanos , Memória Imunológica/imunologia , Camundongos , Receptores de Antígenos de Linfócitos T/imunologia
12.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 32(2): 154-158, 2020 Apr 28.
Artigo em Chinês | MEDLINE | ID: mdl-32458604

RESUMO

OBJECTIVE: To investigate the clinical characteristics and the distribution of peripheral blood T lymphocyte sub-sets in patients with schistosomal hepatic cirrhosis in Suzhou City. METHODS: A total of 32 inpatients with liver diseases due to advanced schistosomiasis at the Department of Infectious Diseases, The First Affiliated Hospital of Soochow University from January 2016 to January 2018 were recruited and assigned into the infection and non-infection groups according to presence of co-infections, and 20 old healthy volunteers served as controls. Venous blood samples were collected on the day of admission, and the proportions of CD4+ T cells, CD8+ T cells, regulatory T (Treg) cells and Th17 cells were detected in peripheral blood using flow cytometry. RESULTS: Most patients with liver disorders due to advanced schistosomiasis were admitted to hospital in Suzhou City because of portal hypertension-associated complications, with a high prevalence of co-infections (59.38%, 19/32). The proportions of peripheral CD4+ and CD8+ T cells and Th17 cells were all significantly lower in patients with liver disorders due to advanced schistosomiasis than in controls (t = -5.111, -4.470 and -2.749, all P < 0.05), and a higher proportion of Treg cells was detected in patients than in controls (t = 5.628, P < 0.05). In addition, there were significant differences among the infection group, non-infection group and controls in terms of the percentage of CD4+ T cells, CD8+ T cells, Th17 cells and Treg cells (F = 15.837, 16.594, 9.290 and 27.866, all P < 0.05). CONCLUSIONS: Portal hypertension-associated complications are predominantly seen in patients with liver diseases due to advanced schistosomiasis at admission in Suzhou City, and co-infections are common. Imbalance of peripheral T cell subsets is detected in patients with liver diseases due to advanced schistosomiasis in Suzhou City.


Assuntos
Hepatopatias Parasitárias , Esquistossomose , Subpopulações de Linfócitos T , Contagem de Células Sanguíneas , Linfócitos T CD8-Positivos/citologia , China , Citometria de Fluxo , Humanos , Hepatopatias Parasitárias/sangue , Hepatopatias Parasitárias/etiologia , Esquistossomose/sangue , Esquistossomose/complicações , Subpopulações de Linfócitos T/citologia , Linfócitos T Reguladores/citologia , Células Th17/citologia
13.
Arch Immunol Ther Exp (Warsz) ; 68(2): 12, 2020 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-32248339

RESUMO

The effect of TNF-blockers on T-lymphocyte subsets is largely unknown in inflammatory bowel diseases (IBDs). The aim of the present study was to analyze the prevalence of T-cell subtypes and their correlation to therapeutic response. Sixty-eight patients with Crohn's disease (CD), 46 with ulcerative colitis (UC) were enrolled. (1) The clinical course was followed after the initiation of TNF-blockers (prospective study). (2) The immunophenotype was also compared between long-term anti-TNF treated-responders and non-responders (cross-sectional study). The results were compared with those of therapy-naïve patients with active disease and those in remission with non-biological immunosuppressive therapy, and with healthy controls. Fourteen subtypes of peripheral blood T cells were measured with flow cytometry. The prevalence of Th2 and Th17 cells, of HLA-DR- and CD69-positive CD4 and CD8 cells, was higher, whereas the percentage of CD45RA-positive CD4 and CD8 cells was lower in both IBDs than in controls. CD8CD69 cell frequency was lower in remission, and decreased during anti-TNF therapy in CD responders. CD8CD45RO memory cells had higher prevalence in UC non-responders than in those starting anti-TNF. CD4CD45RO percentage < 49.05 at the initiation of TNF-blockers was predictive of a subsequent therapeutic response in CD, and Th2 and Th17 prevalence correlated with the duration of remission on TNF-blockers in UC. This study provided a detailed description of the T-cell composition in IBDs. CD8CD69 prevalence may be an activity marker in CD, and CD4CD45RO, Th2 and Th17 levels could be predictive for a therapeutic response to anti-TNF.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Subpopulações de Linfócitos T/citologia , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adulto , Idoso , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/imunologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Subpopulações de Linfócitos T/metabolismo , Células Th17/citologia , Células Th17/metabolismo , Células Th2/citologia , Células Th2/metabolismo , Resultado do Tratamento , Adulto Jovem
14.
Zhonghua Nei Ke Za Zhi ; 59(3): 200-206, 2020 Mar 01.
Artigo em Chinês | MEDLINE | ID: mdl-32146746

RESUMO

Objective: To investigate the characteristics and prognostic value of peripheral blood T lymphocyte subsets in patients with severe influenza. Methods: This was a single-center cross-sectional study in influenza patients admitted to Peking Union Medical College Hospital from August 2017 to April 2018. Peripheral blood lymphocyte subsets were detected by flow cytometry in both patients and 108 healthy controls. Influenza patients were divided into mild group and severe group. Severe patients were further classified into alive and fatal subgroups. Results: A total of 42 influenza patients were recruited in this study, including 24 severe cases (6 deaths). The remaining 18 cases were mild. The peripheral blood lymphocyte counts and lymphocyte subset counts (B, NK, CD4(+)T, CD8(+)T) in either mild patients[795 (571,1 007), 43 (23,144), 70 (47,135), 330 (256,457), 226 (148,366) cells/µl respectively] or severe patients[661 (474,1 151),92 (52,139), 54 (34,134), 373 (235,555), 180 (105,310) cells/µl respectively] were both significantly lower than those of healthy controls [1 963 (1 603,2 394),179 (119,239), 356 (231,496), 663 (531,824), 481 (341,693) cells/µl respectively]. Meanwhile, the T cells and CD8(+)T counts in fatal patients [370 (260,537) cells/µl and 87 (74,105) cells/µl] were significantly lower than those in severe and alive patients [722 (390,990) cells/µl and 222 (154,404) cells/µl]. CD8(+)HLA-DR/CD8(+)and CD8(+)CD38(+)/CD8(+)T cell activating subgroups in mild cases[(53.7±19.2)% and 74.8% (64.1%,83.7%) respectively] were significantly higher than those in severe cases[(38.5±21.7)% and 53.3% (45.3%,67.2%) respectively].Moreover,CD8(+)HLA-DR/CD8(+)count in severe and alive group was higher than that in fatal group [(46.1±19.1)% vs. (18.2±14.6)%, P<0.01]. Logistic regression analysis showed that CD8(+)T cell count (OR=0.952, 95%CI 0.910-0.997, P=0.035) and CD8(+)HLA-DR/CD8(+)T (OR=0.916, 95%CI 0.850-0.987, P=0.022) were both negatively correlated with mortality.Peripheral blood lymphocyte counts in mild cases rapidly decreased within 1 day after diagnosis, and returned to the basic level one week later. Conclusions: All peripheral blood lymphocyte subsets (T,B,NK) in patients with influenza are significantly reduced. These findings are consistent with the immunological characteristics of respiratory viral infections, in which peripheral lymphocytes (especially T cells) migrate to respiratory tract in the early stage and circulate to the peripheral blood after recovery. The activated CD8(+)T cell counts in peripheral blood are negatively correlated with the severity of disease, which could be considered as a prognostic indicator of severe influenza.


Assuntos
Influenza Humana/diagnóstico , Influenza Humana/imunologia , Subpopulações de Linfócitos T/citologia , Linfócitos T CD8-Positivos/citologia , Estudos de Casos e Controles , Estudos Transversais , Citometria de Fluxo , Humanos , Contagem de Linfócitos , Prognóstico , Índice de Gravidade de Doença
15.
Cell Immunol ; 349: 104049, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32057353

RESUMO

Pathogenic microorganisms utilize multiple approaches to break down host immunity in favor of their invasion, of which, cystatin C is one of the soluble factors secreted by parasites reported to affect host immunity in vivo. The cellular targets and mechanisms of action in vivo of cystatin C, however, are far from clear. As professional antigen-presenting cells, dendritic cells (DCs) are first immune cells that contact foreign pathogenic agents or their products to initiate immune responses. We previously reported that cystatin C can regulate the functions of DCs in terms of suppressed CD4+ T cell activation but enhanced Th1/Th17 differentiation via different mechanisms. Here, we further verified these regulatory effects of cystatin C on DCs in vivo. We found that the suppressive role of DC-mediated CD4+ T cell proliferation by cystatin C was partly cell-contact independent and extended to CD8+ T cells in vivo. Although cystatin C-overexpressing DCs trafficked equally as their mock-transduced counterparts, their adoptive transfer suppressed CD8+ T cell immunity and resulted in compromised tumor rejection in both vaccination and treatment regimes. Compared with their role in promoting Th17 differentiation in vivo, cystatin C-transduced DCs had far greater ability to induce T regulatory cells (Tregs), leading to collectively a higher Treg/Th17 ratio in an adoptively transferred disease model, and thus relieved Th17-dependent autoimmunity. Collectively, these data demonstrated strong in vivo evidences for immune regulatory roles of cystatin C in DCs and provided theoretical basis for the application of cystatin C-transduced cell therapy in the treatment or remission of certain autoimmune diseases. (246).


Assuntos
Transferência Adotiva , Artrite Experimental/terapia , Doenças Autoimunes/terapia , Cistatina C/fisiologia , Células Dendríticas/imunologia , Evasão Tumoral/imunologia , Transferência Adotiva/efeitos adversos , Animais , Comunicação Celular , Células Cultivadas , Cistatina C/genética , Células Dendríticas/transplante , Regulação para Baixo , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/genética , Granzimas/biossíntese , Granzimas/genética , Imunoterapia Adotiva , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Ativação Linfocitária , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Ovalbumina/imunologia , Proteínas Citotóxicas Formadoras de Poros/biossíntese , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Recombinantes/metabolismo , Organismos Livres de Patógenos Específicos , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Transdução Genética
16.
Fluids Barriers CNS ; 17(1): 3, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32008573

RESUMO

BACKGROUND: The brain barriers establish compartments in the central nervous system (CNS) that significantly differ in their communication with the peripheral immune system. In this function they strictly control T-cell entry into the CNS. T cells can reach the CNS by either crossing the endothelial blood-brain barrier (BBB) or the epithelial blood-cerebrospinal fluid barrier (BCSFB) of the choroid plexus (ChP). OBJECTIVE: Analysis of the cellular and molecular mechanisms involved in the migration of different human CD4+ T-cell subsets across the BBB versus the BCSFB. METHODS: Human in vitro models of the BBB and BCSFB were employed to study the migration of circulating and CNS-entry experienced CD4+ T helper cell subsets (Th1, Th1*, Th2, Th17) across the BBB and BCSFB under inflammatory and non-inflammatory conditions in vitro. RESULTS: While under non-inflammatory conditions Th1* and Th1 cells preferentially crossed the BBB, under inflammatory conditions the migration rate of all Th subsets across the BBB was comparable. The migration of all Th subsets across the BCSFB from the same donor was 10- to 20-fold lower when compared to their migration across the BBB. Interestingly, Th17 cells preferentially crossed the BCSFB under both, non-inflamed and inflamed conditions. Barrier-crossing experienced Th cells sorted from CSF of MS patients showed migratory characteristics indistinguishable from those of circulating Th cells of healthy donors. All Th cell subsets could additionally cross the BCSFB from the CSF to ChP stroma side. T-cell migration across the BCSFB involved epithelial ICAM-1 irrespective of the direction of migration. CONCLUSIONS: Our observations underscore that different Th subsets may use different anatomical routes to enter the CNS during immune surveillance versus neuroinflammation with the BCSFB establishing a tighter barrier for T-cell entry into the CNS compared to the BBB. In addition, CNS-entry experienced Th cell subsets isolated from the CSF of MS patients do not show an increased ability to cross the brain barriers when compared to circulating Th cell subsets from healthy donors underscoring the active role of the brain barriers in controlling T-cell entry into the CNS. Also we identify ICAM-1 to mediate T cell migration across the BCSFB.


Assuntos
Barreira Hematoencefálica/imunologia , Linfócitos T CD4-Positivos/citologia , Células Epiteliais/citologia , Subpopulações de Linfócitos T/citologia , Transporte Biológico/imunologia , Movimento Celular/imunologia , Sistema Nervoso Central/imunologia , Plexo Corióideo/imunologia , Plexo Corióideo/fisiologia , Células Endoteliais/citologia , Humanos
17.
J Leukoc Biol ; 107(6): 1023-1032, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32064671

RESUMO

The Vγ9Vδ2 T cell subset is the major γδ T cell subset in human peripheral blood and has the unique ability to contribute to immune surveillance by detecting pyrophosphorylated metabolites of isoprenoid synthesis, termed phosphoantigens (pAgs). Vγ9Vδ2 T cells are first detected at midgestation and show postnatal expansion. Interestingly, neonatal Vγ9Vδ2 T cells display a higher TCR repertoire diversity with more public clonotypes and lower pAg responsiveness than in adults. Notably, it is not known whether postnatal changes occur by TCR-dependent reactivity to pAg exposure. Here, we applied next-generation sequencing of γδ TCR repertoires to understand potential differences in the pAg-mediated response of neonatal and adult Vγ9Vδ2 T cells at the level of the expressed γδ TCR. We observed a polyclonal pAg-induced response of neonatal and adult Vγ9Vδ2 T cells, albeit neonatal γδ T cells showed less in vitro pAg responsiveness. Neonatal Vγ9Vδ2 T cells displayed a less pronounced bias for Jδ1 usage and a more frequent use of Jδ2 or Jδ3 that remained stable after pAg exposure. In addition, public and private Vδ2 TRD clones took part in the polyclonal pAg-induced response in neonates and adults. In conclusion, adult and neonatal Vγ9Vδ2 T cells both undergo polyclonal pAg-induced proliferation, whereas especially adult Vγ9Vδ2 T cells display a high stability at the level of the expressed TCR repertoire.


Assuntos
Sangue Fetal/imunologia , Fosfoproteínas/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Proliferação de Células/efeitos dos fármacos , Células Clonais , Sangue Fetal/citologia , Sangue Fetal/efeitos dos fármacos , Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Recém-Nascido , Interleucina-2/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Organofosfatos/farmacologia , Fosfoproteínas/genética , Cultura Primária de Células , Receptores de Antígenos de Linfócitos T gama-delta/genética , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Ácido Zoledrônico/farmacologia
18.
Nat Commun ; 11(1): 113, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913278

RESUMO

While antigen-primed T cells proliferate at speeds close to the physiologic maximum of mammalian cells, T cell memory is maintained in the absence of antigen by rare cell divisions. The transition between these distinct proliferative programs has been difficult to resolve via population-based analyses. Here, we computationally reconstruct the proliferative history of single CD8+ T cells upon vaccination and measure the division speed of emerging T cell subsets in vivo. We find that slower cycling central memory precursors, characterized by an elongated G1 phase, segregate early from the bulk of rapidly dividing effector subsets, and further slow-down their cell cycle upon premature removal of antigenic stimuli. In contrast, curtailed availability of inflammatory stimuli selectively restrains effector T cell proliferation due to reduced receptivity for interleukin-2. In line with these findings, persistence of antigenic but not inflammatory stimuli throughout clonal expansion critically determines the later size of the memory compartment.


Assuntos
Linfócitos T CD8-Positivos/citologia , Diferenciação Celular , Divisão Celular , Memória Imunológica , Subpopulações de Linfócitos T/citologia , Animais , Linfócitos T CD8-Positivos/imunologia , Ciclo Celular , Feminino , Interleucina-2/genética , Interleucina-2/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Subpopulações de Linfócitos T/imunologia
19.
Can J Vet Res ; 84(1): 52-59, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31920218

RESUMO

The aim of the study was to determine age-related changes in peripheral blood lymphocytes in pigs. Previous studies looking at age-related differences in lymphocyte subsets in porcine blood have not established reference ranges for these parameters. Moreover, most studies have concentrated on the dynamic changes in the first months of life, failing to continue observations in older animals. Therefore, in the present study, relative counts of various lymphocyte subpopulations (cytotoxic and helper T-cells, B-cells, and γδ T-cells) were evaluated to characterize the development of the cellular immune system at 28, 35, 135, and 200 days of age in growing pigs and adult sows (i.e., first and subsequent parity). In all examined groups, CD3+ cells constituted the largest percentage of cells. A statistically significant higher percentage of TCRγδ+CD3+ was noted in fatteners and gilts in comparison to other age groups. These results may be a reflection of antigenic pressure and show an immune response to viral or bacterial agents/environmental microbism.


Assuntos
Envelhecimento/sangue , Contagem de Linfócitos/veterinária , Suínos/sangue , Análise de Variância , Animais , Anticorpos Monoclonais , Linfócitos B/citologia , Complexo CD3/sangue , Feminino , Citometria de Fluxo/veterinária , Fenótipo , Distribuição Aleatória , Subpopulações de Linfócitos T/citologia
20.
Eur J Immunol ; 50(3): 363-379, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31755098

RESUMO

After repeated antigen exposure, both memory and terminally differentiated cells can be generated within CD8+ T cells. Although, during their differentiation, activated CD8+ T cells may first lose CD28, and CD28- cells may eventually express CD57 as a subsequent step, a population of CD28+ CD57+ (DP) CD8+ T cells can be identified in the peripheral blood. How this population is distinct from CD28- CD57- (DN) CD8+ T cells, and from the better characterized non-activated/early-activated CD28+ CD57- and senescent-like CD28- CD57+ CD8+ T cell subsets is currently unknown. Here, RNA expression of the four CD8+ T cell subsets isolated from human PBMCs was analyzed using microarrays. DN cells were more similar to "early" highly differentiated cells, with decreased TNF and IFN-γ production, impaired DNA damage response and apoptosis. Conversely, increased apoptosis and expression of cytokines, co-inhibitory, and chemokine receptors were found in DP cells. Higher levels of DP CD8+ T cells were observed 7 days after Hepatitis B vaccination, and decreased levels of DP cells were found in rheumatoid arthritis patients. More DP and DN CD8+ T cells were present in the bone marrow, in comparison with PBMCs. In summary, our results indicate that DP and DN cells are distinct CD8+ T cell subsets displaying defined properties.


Assuntos
Antígenos CD28/imunologia , Antígenos CD57/imunologia , Linfócitos T CD8-Positivos/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T CD8-Positivos/citologia , Humanos , Fenótipo , Subpopulações de Linfócitos T/citologia
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