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1.
Nature ; 585(7824): 277-282, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32879489

RESUMO

Abnormal epigenetic patterns correlate with effector T cell malfunction in tumours1-4, but the cause of this link is unknown. Here we show that tumour cells disrupt methionine metabolism in CD8+ T cells, thereby lowering intracellular levels of methionine and the methyl donor S-adenosylmethionine (SAM) and resulting in loss of dimethylation at lysine 79 of histone H3 (H3K79me2). Loss of H3K79me2 led to low expression of STAT5 and impaired T cell immunity. Mechanistically, tumour cells avidly consumed methionine and outcompeted T cells for methionine by expressing high levels of the methionine transporter SLC43A2. Genetic and biochemical inhibition of tumour SLC43A2 restored H3K79me2 in T cells, thereby boosting spontaneous and checkpoint-induced tumour immunity. Moreover, methionine supplementation improved the expression of H3K79me2 and STAT5 in T cells, and this was accompanied by increased T cell immunity in tumour-bearing mice and patients with colon cancer. Clinically, tumour SLC43A2 correlated negatively with T cell histone methylation and functional gene signatures. Our results identify a mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumour microenvironment. Thus, cancer methionine consumption is an immune evasion mechanism, and targeting cancer methionine signalling may provide an immunotherapeutic approach.


Assuntos
Sistema L de Transporte de Aminoácidos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Histonas/metabolismo , Metionina/metabolismo , Metilação , Neoplasias/metabolismo , Sistema L de Transporte de Aminoácidos/deficiência , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Epigênese Genética , Feminino , Histonas/química , Humanos , Camundongos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Receptores de Antígenos de Linfócitos T/metabolismo , Fator de Transcrição STAT5/metabolismo
2.
Ecotoxicol Environ Saf ; 202: 110912, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800247

RESUMO

Occupational exposure to pesticides has been identified as a factor that predisposes to disorders of the immune system. Immunosuppression, autoimmunity, cancer of various organs and other diseases in people who apply these products have been reported by the studies. This study aimed to investigate the relationship between occupational exposure to pesticides and the immunological profile in 43 farmers exposed to mixtures of pesticides for at least 15 years. A control group composed of 30 individuals without a history of occupational exposure to pesticides was also evaluated. Peripheral blood samples were processed by flow cytometry and cells were labelled with an 8-color monoclonal antibody panel. Plasma cytokines were also measured. Significant increase in classical monocytes (p < 0.001) and dendritic cells (p < 0.001) in the exposed group was observed as well in total T cells (p = 0.04), central memory CD8 T cells (p = 0.02) and effector memory CD8 T cells (p = 0.01). On the other hand, the activation markers of T cells as the expression of CD57, HLA-DR, CD25 and CD28 were evaluated and no difference was found between groups. When the B cells were analyzed, a significant decrease in total B cells (p = 0.01), regulatory B cells (p < 0.001) and plasmablasts (p < 0.001) in the exposed group, compared to healthy controls, was observed. Pro-inflammatory IL-6 was significantly elevated (p = 0.04) in the plasma of farmers compared to that of controls. The constant antigenic stimulus that occurs during exposure to pesticides can favor the recruitment of dendritic cells and macrophages (APCs) presents in the skin and respiratory tract. In the secondary lymphoid organs, the CD4 T and B cells that process such antigens are possibly undergoing proliferative exhaustion, with the consequent depletion of all mature B subpopulations. The resulting drop in humoral immunity may be offset by an increase in the number of circulating CD8 T lymphocytes due to their cytotoxic action.


Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Exposição Ocupacional/estatística & dados numéricos , Praguicidas/toxicidade , Adulto , Poluentes Ocupacionais do Ar/análise , Linfócitos B/imunologia , Brasil , Antígenos CD28/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Fazendeiros , Feminino , Citometria de Fluxo , Antígenos HLA-DR/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2 , Masculino , Pessoa de Meia-Idade , Praguicidas/análise , Praguicidas/metabolismo
3.
BMC Infect Dis ; 20(1): 590, 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778058

RESUMO

BACKGROUND: Antiviral therapy is recommended for patients with immune-active chronic hepatitis B (CHB) to decrease the risk of liver-related complications. However, the outcomes of the pegylated IFN-α (PEG-IFN-α) therapy vary among CHB patients. We aimed to identify factors that can influence the outcomes in CHB patients who received antiviral PEG-IFN-α monotherapy. METHODS: Thirty-two CHB patients who received PEG-IFN-α monotherapy were enrolled in this study. All of the patients underwent two liver biopsies at baseline and 6 months after the initiation of the therapy. CD8+ T cells, CD4+ T cells, CD68+ mononuclear cells, and PD-1 levels in the 64 liver biopsy specimens were examined via immunofluorescence. RESULTS: The overall median frequency of CD8+ T cells in the liver tissues of 32 CHB patients significantly decreased at 6 months after the therapy initiation (p < 0.01). In the FIER (fibrosis and inflammation response with HBeAg seroconversion) group, CD8+PD-1+ T cells significantly decreased at 6 months (p < 0.05), while CD8+PD-1- T cells had no significant difference. On the contrary, in the FIENR (no fibrosis and inflammation response and HBeAg seroconversion) group, CD8+PD-1- T cells significantly decreased after 6 months of PEG-IFN-α treatment (p < 0.05), while CD8+PD-1+ T cells had no significant difference. In addition, the levels of CD68+ mononuclear cells in the FIER group showed an overall increasing trend after treatment (p < 0.05). CONCLUSIONS: The changes in the levels of CD8+PD-1+ T cells and CD68+ mononuclear cells may be related to the response to PEG-IFN-α therapy.


Assuntos
Antivirais/uso terapêutico , Linfócitos T CD8-Positivos/metabolismo , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Fígado/patologia , Polietilenoglicóis/uso terapêutico , Adulto , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Antígenos E da Hepatite B/sangue , Antígenos E da Hepatite B/imunologia , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Fígado/metabolismo , Masculino , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Recombinantes/uso terapêutico , Adulto Jovem
4.
EBioMedicine ; 57: 102885, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32650275

RESUMO

BACKGROUND: Elucidating the role of T cell responses in COVID-19 is of utmost importance to understand the clearance of SARS-CoV-2 infection. METHODS: 30 hospitalized COVID-19 patients and 60 age- and gender-matched healthy controls (HC) participated in this study. We used two comprehensive 11-colour flow cytometric panels conforming to Good Laboratory Practice and approved for clinical diagnostics. FINDINGS: Absolute numbers of lymphocyte subsets were differentially decreased in COVID-19 patients according to clinical severity. In severe disease (SD) patients, all lymphocyte subsets were reduced, whilst in mild disease (MD) NK, NKT and γδ T cells were at the level of HC. Additionally, we provide evidence of T cell activation in MD but not SD, when compared to HC. Follow up samples revealed a marked increase in effector T cells and memory subsets in convalescing but not in non-convalescing patients. INTERPRETATION: Our data suggest that activation and expansion of innate and adaptive lymphocytes play a major role in COVID-19. Additionally, recovery is associated with formation of T cell memory as suggested by the missing formation of effector and central memory T cells in SD but not in MD. Understanding T cell-responses in the context of clinical severity might serve as foundation to overcome the lack of effective anti-viral immune response in severely affected COVID-19 patients and can offer prognostic value as biomarker for disease outcome and control. FUNDING: Funded by State of Lower Saxony grant 14-76,103-184CORONA-11/20 and German Research Foundation, Excellence Strategy - EXC2155"RESIST"-Project ID39087428, and DFG-SFB900/3-Project ID158989968, grants SFB900-B3, SFB900-B8.


Assuntos
Betacoronavirus/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Ativação Linfocitária/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Feminino , Humanos , Memória Imunológica/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Prognóstico , Índice de Gravidade de Doença , Adulto Jovem
5.
PLoS One ; 15(7): e0236678, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32716971

RESUMO

Head and neck squamous cell carcinoma (HNSCC), a tumor included oral cavity, lips, larynx, oropharynx, and the nasopharynx et al. The cell division cycle-associated (CDCA) protein family (CDCA1-8) critical for normal cell function and cancer cell proliferation. We explored the mutation signatures and expression levels of various CDCAs in detail in HNSCC. A comprehensive bioinformatics analysis pipeline based on copy number and gene expressions data from patients with HNSCC in order to given new insights into the possible functions and distinct prognostics that underlie CDCAs regulation. We compared the transcriptional expression of CDCAs in HNSCC and found significantly elevated mRNA expression of CDCA1-8 in HNSCC tissues across multiple datasets. We also found CDCA5/6/8 are over-expressed both transcriptionally and translationally in patients with HNSCC. Our results suggested that that mRNA levels of CDCA1/2/4/7 related to the prognosis and can be used as a new useful biomarker for predicting the survival of HNSCC patients. The top 5 CDCAs neighboring gene alterations in HNSCCs were found in MYC, STAG1, RAD21, KLHL9 and NDC80. Multivariable Cox proportional hazard model also showed that CD8+ T cells were higher (P<0.05) in HNSCC-HPV-pos patients and that this was related to CDCA1/2/3/4/5/7. This study utilizes online tools to conduct specific gene analyses from free open databases, but our study requires more large-scale genomics research and basic research.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Bases de Dados Factuais , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Estimativa de Kaplan-Meier , Prognóstico , Modelos de Riscos Proporcionais , RNA Mensageiro/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade
6.
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
7.
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
8.
EMBO Mol Med ; 12(6): e12661, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: covidwho-214535

RESUMO

The ongoing severe acute respiratory sickness coronavirus 2 (SARS-CoV-2) pandemic has resulted in more than 3,600,000 detected cases of COVID-19 illness and nearly 260,000 deaths worldwide as of May 6, 2020. Recently, BCG vaccination was shown to correlate with reduced COVID-19 case fatality rates (preprint: Miller et al, 2020; preprint: Sala & Miyakawa, 2020; https://www.jsatonotes.com/2020/03/if-i-were-north-americaneuropeanaustral.html). The most recent data from publicly available resources also indicate that both COVID-19 incidence and total deaths are strongly associated with the presence or absence of national mandatory BCG vaccination programs. As seen in Table 1, seven of eight countries with very low numbers of total deaths (< 40 per 1 million population) adopted a mandatory BCG vaccination program using one of a set of 6 separate BCG strains (Table 1). In contrast, COVID-19 mortality was markedly higher in countries where BCG vaccination is not widely administered or is given only to high-risk groups. COVID-19 mortality was also higher in countries where widespread BCG vaccination was discontinued more than 20 years ago and in countries that used the BCG Denmark strain regularly or temporarily. This raises the question of whether BCG vaccination and reduced COVID-19 mortality are causally related. An additional question is why different BCG strains may be variably associated with mortality.


Assuntos
Vacina BCG/imunologia , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Betacoronavirus/isolamento & purificação , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Humanos , Mycobacterium bovis/genética , Mycobacterium bovis/imunologia , Mycobacterium bovis/metabolismo , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Risco , Sorogrupo , Análise de Sobrevida , Vacinação
9.
Proc Natl Acad Sci U S A ; 117(22): 12306-12314, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32439709

RESUMO

Tissue-resident memory CD8 T (TRM) cells are a unique immune memory subset that develops and remains in peripheral tissues at the site of infection, providing future host resistance upon reexposure to that pathogen. In the pulmonary system, TRM are identified through S1P antagonist CD69 and expression of integrins CD103/ß7 and CD49a/CD29(ß1). Contrary to the established role of CD69 on CD8 T cells, the functions of CD103 and CD49a on this population are not well defined. This study examines the expression patterns and functions of CD103 and CD49a with a specific focus on their impact on T cell motility during influenza virus infection. We show that the TRM cell surface phenotype develops by 2 wk postinfection, with the majority of the population expressing CD49a and a subset that is also positive for CD103. Despite a previously established role in retaining TRM in peripheral tissues, CD49a facilitates locomotion of virus-specific CD8 T cells, both in vitro and in vivo. These results demonstrate that CD49a may contribute to local surveillance mechanisms of the TRM population.


Assuntos
Antígenos CD/imunologia , Vírus da Influenza A Subtipo H3N2/fisiologia , Influenza Humana/imunologia , Cadeias alfa de Integrinas/imunologia , Integrina alfa1/metabolismo , Animais , Antígenos CD/genética , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Adesão Celular , Movimento Celular , Humanos , Memória Imunológica , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/genética , Influenza Humana/fisiopatologia , Influenza Humana/virologia , Cadeias alfa de Integrinas/genética , Integrina alfa1/genética , Camundongos Endogâmicos C57BL
10.
EMBO Mol Med ; 12(6): e12661, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32379923

RESUMO

The ongoing severe acute respiratory sickness coronavirus 2 (SARS-CoV-2) pandemic has resulted in more than 3,600,000 detected cases of COVID-19 illness and nearly 260,000 deaths worldwide as of May 6, 2020. Recently, BCG vaccination was shown to correlate with reduced COVID-19 case fatality rates (preprint: Miller et al, 2020; preprint: Sala & Miyakawa, 2020; https://www.jsatonotes.com/2020/03/if-i-were-north-americaneuropeanaustral.html). The most recent data from publicly available resources also indicate that both COVID-19 incidence and total deaths are strongly associated with the presence or absence of national mandatory BCG vaccination programs. As seen in Table 1, seven of eight countries with very low numbers of total deaths (< 40 per 1 million population) adopted a mandatory BCG vaccination program using one of a set of 6 separate BCG strains (Table 1). In contrast, COVID-19 mortality was markedly higher in countries where BCG vaccination is not widely administered or is given only to high-risk groups. COVID-19 mortality was also higher in countries where widespread BCG vaccination was discontinued more than 20 years ago and in countries that used the BCG Denmark strain regularly or temporarily. This raises the question of whether BCG vaccination and reduced COVID-19 mortality are causally related. An additional question is why different BCG strains may be variably associated with mortality.


Assuntos
Vacina BCG/imunologia , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Betacoronavirus/isolamento & purificação , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Humanos , Mycobacterium bovis/genética , Mycobacterium bovis/imunologia , Mycobacterium bovis/metabolismo , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Risco , Sorogrupo , Análise de Sobrevida , Vacinação
11.
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
12.
Emerg Microbes Infect ; 9(1): 757-760, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: covidwho-29228

RESUMO

The dysfunction of the renin-angiotensin system (RAS) has been observed in coronavirus infection disease (COVID-19) patients, but whether RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs), are associated with clinical outcomes remains unknown. COVID-19 patients with hypertension were enrolled to evaluate the effect of RAS inhibitors. We observed that patients receiving ACEI or ARB therapy had a lower rate of severe diseases and a trend toward a lower level of IL-6 in peripheral blood. In addition, ACEI or ARB therapy increased CD3 and CD8 T cell counts in peripheral blood and decreased the peak viral load compared to other antihypertensive drugs. This evidence supports the benefit of using ACEIs or ARBs to potentially contribute to the improvement of clinical outcomes of COVID-19 patients with hypertension.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Infecções por Coronavirus/complicações , Hipertensão/tratamento farmacológico , Pneumonia Viral/complicações , Sistema Renina-Angiotensina , Idoso , Betacoronavirus , Proteína C-Reativa/análise , Complexo CD3 , Linfócitos T CD8-Positivos/citologia , China , Infecções por Coronavirus/tratamento farmacológico , Feminino , Humanos , Hipertensão/complicações , Hipertensão/virologia , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento , Carga Viral
13.
Emerg Microbes Infect ; 9(1): 757-760, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32228222

RESUMO

The dysfunction of the renin-angiotensin system (RAS) has been observed in coronavirus infection disease (COVID-19) patients, but whether RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs), are associated with clinical outcomes remains unknown. COVID-19 patients with hypertension were enrolled to evaluate the effect of RAS inhibitors. We observed that patients receiving ACEI or ARB therapy had a lower rate of severe diseases and a trend toward a lower level of IL-6 in peripheral blood. In addition, ACEI or ARB therapy increased CD3 and CD8 T cell counts in peripheral blood and decreased the peak viral load compared to other antihypertensive drugs. This evidence supports the benefit of using ACEIs or ARBs to potentially contribute to the improvement of clinical outcomes of COVID-19 patients with hypertension.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Infecções por Coronavirus/complicações , Hipertensão/tratamento farmacológico , Pneumonia Viral/complicações , Sistema Renina-Angiotensina , Idoso , Betacoronavirus , Proteína C-Reativa/análise , Complexo CD3 , Linfócitos T CD8-Positivos/citologia , China , Infecções por Coronavirus/tratamento farmacológico , Feminino , Humanos , Hipertensão/complicações , Hipertensão/virologia , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento , Carga Viral
14.
Nat Commun ; 11(1): 1632, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32242021

RESUMO

Co-stimulatory signals, cytokines and transcription factors regulate the balance between effector and memory cell differentiation during T cell activation. Here, we analyse the role of the TRAF2-/NCK-interacting kinase (TNIK), a signaling molecule downstream of the tumor necrosis factor superfamily receptors such as CD27, in the regulation of CD8+ T cell fate during acute infection with lymphocytic choriomeningitis virus. Priming of CD8+ T cells induces a TNIK-dependent nuclear translocation of ß-catenin with consecutive Wnt pathway activation. TNIK-deficiency during T cell activation results in enhanced differentiation towards effector cells, glycolysis and apoptosis. TNIK signaling enriches for memory precursors by favouring symmetric over asymmetric cell division. This enlarges the pool of memory CD8+ T cells and increases their capacity to expand after re-infection in serial re-transplantation experiments. These findings reveal that TNIK is an important regulator of effector and memory T cell differentiation and induces a population of stem cell-like memory T cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Coriomeningite Linfocítica/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Animais , Apoptose , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular , Humanos , Memória Imunológica , Ativação Linfocitária , Coriomeningite Linfocítica/genética , Coriomeningite Linfocítica/fisiopatologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais , Via de Sinalização Wnt
15.
Circulation ; 142(1): 68-78, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32293910

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has affected health and economy worldwide on an unprecedented scale. Patients have diverse clinical outcomes, but those with preexisting cardiovascular disease, hypertension, and related conditions incur disproportionately worse outcome. The high infectivity of severe acute respiratory syndrome coronavirus 2 is in part related to new mutations in the receptor binding domain, and acquisition of a furin cleavage site in the S-spike protein. The continued viral shedding in the asymptomatic and presymptomatic individuals enhances its community transmission. The virus uses the angiotensin converting enzyme 2 receptor for internalization, aided by transmembrane protease serine 2 protease. The tissue localization of the receptors correlates with COVID-19 presenting symptoms and organ dysfunction. Virus-induced angiotensin converting enzyme 2 downregulation may attenuate its function, diminish its anti-inflammatory role, and heighten angiotensin II effects in the predisposed patients. Lymphopenia occurs early and is prognostic, potentially associated with reduction of the CD4+ and some CD8+ T cells. This leads to imbalance of the innate/acquired immune response, delayed viral clearance, and hyperstimulated macrophages and neutrophils. Appropriate type I interferon pathway activation is critical for virus attenuation and balanced immune response. Persistent immune activation in predisposed patients, such as elderly adults and those with cardiovascular risk, can lead to hemophagocytosis-like syndrome, with uncontrolled amplification of cytokine production, leading to multiorgan failure and death. In addition to the airways and lungs, the cardiovascular system is often involved in COVID-19 early, reflected in the release of highly sensitive troponin and natriuretic peptides, which are all extremely prognostic, in particular, in those showing continued rise, along with cytokines such as interleukin-6. Inflammation in the vascular system can result in diffuse microangiopathy with thrombosis. Inflammation in the myocardium can result in myocarditis, heart failure, cardiac arrhythmias, acute coronary syndrome, rapid deterioration, and sudden death. Aggressive support based on early prognostic indicators with expectant management can potentially improve recovery. Appropriate treatment for heart failure, arrhythmias, acute coronary syndrome, and thrombosis remain important. Specific evidence-based treatment strategies for COVID-19 will emerge with ongoing global collaboration on multiple approaches being evaluated. To protect the wider population, antibody testing and effective vaccine will be needed to make COVID-19 history.


Assuntos
Sistema Cardiovascular/metabolismo , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , Coagulação Sanguínea , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/patologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Imunidade Inata , Interleucina-6/metabolismo , Linfopenia/etiologia , Masculino , Pandemias , Peptidil Dipeptidase A/metabolismo , Fenótipo , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Prognóstico , Serina Endopeptidases/metabolismo , Taxa de Sobrevida
16.
Klin Lab Diagn ; 65(5): 294-298, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32298545

RESUMO

To determine the new criteria for predicting the outcome of pregnancy in women with habitual abortion based on features of differentiation of naive T cells and memory cells in a population of T-helper (CD4+) and cytotoxic T lymphocytes (CD8+). The study involved 61 women with threatened and habitual abortion in the first trimester of gestation. Depending on the outcome of pregnancy was allocated to 3 groups: I went to 39 women whose pregnancy ended in timely delivery; in II - 10 women whose pregnancies ended in premature birth; in III - 11 patients in whom there was a spontaneous miscarriage. Using three-color flow cytometry as peripheral venous blood in populations of CD8+ and CD4+ determined by the content Tn, Tcm, Tem and Temra cells. Statistical analysis was carried out in the program «MicrosoftOffice 2010¼, «Statistica for Windows 6.0¼ and MedCalc¼. When conducting a retrospective assessment, it was found that in the group of patients whose pregnancy ended in preterm delivery, the percentage of CD4+ Tem memory cells was significantly higher and CD4+ Tn lower than in the subgroup with timely delivery (p = 0.013 and p = 0.025, respectively ) In patients with early spontaneous miscarriage, the level of CD8+ Tn significantly decreased against the background of the growth of CD8+ Tem memory cells compared with the same parameters in patients with timely delivery (p = 0.040 and p = 0.014, respectively). Prediction of spontaneous abortion is possible up to CD4+ Tn equal to 34.2% or less (sensitivity - 100.0%, specificity - 56.4%, accuracy - 63.8%), premature birth - if the CD4+ Tn equal to 35, 2% or less (sensitivity - 66.7%, specificity - 74.4% accuracy - 72.9%). Thus, the new criteria will allow additional time to identify risk and assign adequate treatment aimed at prolonging the desired pregnancy.


Assuntos
Aborto Habitual/diagnóstico , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Resultado da Gravidez , Nascimento Prematuro/diagnóstico , Feminino , Humanos , Recém-Nascido , Gravidez , Prognóstico , Estudos Retrospectivos , Sensibilidade e Especificidade
17.
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
18.
J Vis Exp ; (156)2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32150154

RESUMO

Immune cell subtype population frequencies can have a large effect on the efficacy of T cell therapies. Current methods, like flow cytometry, have specific sample requirements, high sample input, are low throughput, and are difficult to standardize, all of which are detrimental to characterization of cell therapy products during their development and manufacturing. The assays described herein accurately identify and quantify immune cell types in a heterogeneous mixture of cells using isolated genomic DNA (gDNA). DNA methylation patterns are revealed through bisulfite conversion, a process in which unmethylated cytosines are converted to uracils. Unmethylated DNA regions are detected through qPCR amplification using primers targeting converted areas. One unique locus per assay is measured and serves as an accurate identifier for a specific cell type. The assays are robust and identify CD8+, regulatory, and Th17 T cells in a high throughput manner. These optimized assays can potentially be used for in-process and product release testing for cell therapy process.


Assuntos
Linfócitos T CD8-Positivos/citologia , Metilação de DNA , Epigênese Genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Linfócitos T Reguladores/citologia , Células Th17/citologia , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Humanos , Análise de Sequência de DNA/métodos , Sulfitos/química , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo
19.
PLoS Pathog ; 16(3): e1008339, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32163523

RESUMO

Despite the success of antiretroviral therapy (ART) to halt viral replication and slow disease progression, this treatment is not curative and there remains an urgent need to develop approaches to clear the latent HIV reservoir. The human IL-15 superagonist N-803 (formerly ALT-803) is a promising anti-cancer biologic with potent immunostimulatory properties that has been extended into the field of HIV as a potential "shock and kill" therapeutic for HIV cure. However, the ability of N-803 to reactivate latent virus and modulate anti-viral immunity in vivo under the cover of ART remains undefined. Here, we show that in ART-suppressed, simian-human immunodeficiency virus (SHIV)SF162P3-infected rhesus macaques, subcutaneous administration of N-803 activates and mobilizes both NK cells and SHIV-specific CD8+ T cells from the peripheral blood to lymph node B cell follicles, a sanctuary site for latent virus that normally excludes such effector cells. We observed minimal activation of memory CD4+ T cells and no increase in viral RNA content in lymph node resident CD4+ T cells post N-803 administration. Accordingly, we found no difference in the number or magnitude of plasma viremia timepoints between treated and untreated animals during the N-803 administration period, and no difference in the size of the viral DNA cell-associated reservoir post N-803 treatment. These results substantiate N-803 as a potent immunotherapeutic candidate capable of activating and directing effector CD8+ T and NK cells to the B cell follicle during full ART suppression, and suggest N-803 must be paired with a bona fide latency reversing agent in vivo to facilitate immune-mediated modulation of the latent viral reservoir.


Assuntos
Antirretrovirais/administração & dosagem , Linfócitos B/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Interleucina-15/antagonistas & inibidores , Células Matadoras Naturais/efeitos dos fármacos , Proteínas/administração & dosagem , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/fisiopatologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Interleucina-15/genética , Interleucina-15/imunologia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/fisiopatologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/fisiologia , Latência Viral/efeitos dos fármacos
20.
Adv Exp Med Biol ; 1224: 53-62, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32036604

RESUMO

In the tumor microenvironment, CD8+ T cells play a major role in tumor immunity. CD8+ T cells differentiate to cytotoxic T cells, traffic into the tumor microenvironment, and exhibit cytotoxicity against tumor cells. These processes have both positive and negative effects. Enhancements in the cytotoxic activity of tumor antigen-specific cytotoxic T cells in the tumor microenvironment are crucial for the development of cancer immunotherapy. To achieve this, several immunotherapies, including cancer vaccines, T cells engineered to express chimeric antigen receptors (CAR T cells), and bispecific T-cell engagers (BiTEs), have been developed. In contrast to cancer vaccines, CAR T cells, and BiTEs, immune checkpoint inhibitors enhance the activity of cytotoxic T cells by inhibiting the negative regulators of T cells.The total number, type, and activity of tumor antigen-specific cytotoxic T cells in the tumor microenvironment need to be clarified, particularly for the development of companion diagnostics to identify patients for whom these therapies are effective. Therefore, technologies including TCR repertoire, single-cell, and T-cell cytotoxicity analyses using BiTEs have been developed.Based on these and future innovations, the generation of effective cancer immunotherapies is anticipated.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Neoplasias/imunologia , Microambiente Tumoral , Linfócitos T CD8-Positivos/citologia , Vacinas Anticâncer/imunologia , Humanos , Imunoterapia , Neoplasias/terapia , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia
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