Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.814
Filtrar
1.
J Exp Med ; 218(4)2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33533915

RESUMO

SARS-CoV-2 is responsible for an ongoing pandemic that has affected millions of individuals around the globe. To gain further understanding of the immune response in recovered individuals, we measured T cell responses in paired samples obtained an average of 1.3 and 6.1 mo after infection from 41 individuals. The data indicate that recovered individuals show persistent polyfunctional SARS-CoV-2 antigen-specific memory that could contribute to rapid recall responses. Recovered individuals also show enduring alterations in relative overall numbers of CD4+ and CD8+ memory T cells, including expression of activation/exhaustion markers, and cell division.


Assuntos
/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Celular , /imunologia , Adulto , Idoso , Antígenos Virais/imunologia , Biomarcadores , Feminino , Humanos , Imunofenotipagem , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto Jovem
2.
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
3.
Anticancer Res ; 40(9): 5221-5227, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878810

RESUMO

BACKGROUND/AIM: Bladder cancer (BLCA, urothelial bladder cancer) is one of the most common malignancies with increasing incidence and mortality worldwide. Poor diagnosis and the limitation of treatment is still an unmet need in clinical practice. γδ T-Cells have been paid increasing attention because of their potent cytotoxicity against tumors. Herein, we investigated the cytolytic effect of γδ T-cells in combination with the chemotherapeutic drug, carboplatin, against BLCA cells. MATERIALS AND METHODS: The standard protocol for the induction and expansion of peripheral blood mononuclear cell-derived γδ T-cells was a zoledronic acid/interleukin-2-based medium system for 2 weeks. The cytotoxicity of γδ T-cells with and without carboplatin against BLCA cells was examined. RESULTS: After incubation, T-cell receptor-positive γδ T-cells showed a natural killer cell-like phenotypic characteristic and dose-dependently increased cytotoxicity against BLCA cells. Interestingly, we found that in advanced BLCA cells, which were more resistant to carboplatin, the cell viability was significantly (p<0.05) reduced in the presence of γδ T-cells. CONCLUSION: Our findings showed that γδ T-cell therapy has potent benefit in cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Carboplatina/farmacologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Neoplasias da Bexiga Urinária/patologia
4.
PLoS One ; 15(9): e0239157, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32960910

RESUMO

CD4dimCD8bright T cells, a genuine population of CD8+ T cells, are highly activated and cytolytic. Recently, the low affinity IgG Fc fragment receptor CD32a was described as marker of HIV latency while others reported that CD32a is associated with T cell activation. Given that we have previously established that CD4dimCD8bright T cells are highly activated, mediate anti-HIV responses, and are infected by HIV, we assessed here CD32 expression on CD4dimCD8bright T cells in context of HIV. CD32 frequency on peripheral CD4dimCD8bright and CD4+ T cells was determined by flow cytometry among HIV negative and HIV positive patients. We report that among HIV- individuals, mean CD32 percent expression was 60% on CD4dimCD8bright T cells and 17% on CD4+ T cells (p<0.01). Among HIV+ patients, mean CD32 percent expression was 54% on CD4dimCD8bright T cells and 12% on CD4+ T cells (p<0.001). CD32 expression on CD4dimCD8bright T cells did not correlate with CD4 count and viral load and was not different by HIV serostatus. CD32 was also higher on other double positive T cell populations in both HIV negative and HIV positive donors in comparison to their single positive T cell counterpart. Together, these studies indicate that CD32 is enriched on double positive T cells regardless of HIV serostatus. The functional role of CD32 on these double positive T cells remains to be elucidated.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/sangue , Receptores de IgG/metabolismo , Subpopulações de Linfócitos T/imunologia , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Separação Celular , Citometria de Fluxo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Humanos , Receptores de IgG/imunologia , Subpopulações de Linfócitos T/metabolismo , Carga Viral
5.
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
6.
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
7.
Proc Natl Acad Sci U S A ; 117(33): 20117-20126, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32747558

RESUMO

t(8;21)(q22;q22) acute myelogenous leukemia (AML) is morphologically characterized by a continuum of heterogeneous leukemia cells from myeloblasts to differentiated myeloid elements. Thus, t(8;21) AML is an excellent model for studying heterogeneous cell populations and cellular evolution during disease progression. Using integrative analyses of immunophenotype, RNA-sequencing (RNA-seq), and single-cell RNA-sequencing (scRNA-seq), we identified three distinct intrapatient leukemic cell populations that were arrested at different stages of myeloid differentiation: CD34+CD117dim blasts, CD34+CD117bri blasts, and abnormal myeloid cells with partial maturation (AM). CD117 is also known as c-KIT protein. CD34+CD117dim cells were blocked in the G0/G1 phase at disease onset, presenting with the regular morphology of myeloblasts showing features of granulocyte-monocyte progenitors (GMP), and were drug-resistant to chemotherapy. Genes associated with cell migration and adhesion (LGALS1, EMP3, and ANXA 2) were highly expressed in the CD34+CD117dim population. CD34+CD117bri blasts were blocked a bit later than the CD34+CD117dim population in the hematopoietic differentiation stage and displayed high proliferation ability. AM cells, which bear abnormal myelocyte morphology, especially overexpressed granule genes AZU1, ELANE, and PRTN3 and were sensitive to chemotherapy. scRNA-seq at different time points identified CD34+CD117dim blasts as an important leukemic cluster that expanded at postrelapse refractory stage after several cycles of chemotherapy. Patients with t(8;21) AML with a higher proportion of CD34+CD117dim cells had significantly worse clinical outcomes than those with a lower CD34+CD117dim proportion. Univariate and multivariate analyses identified CD34+CD117dim proportion as an independent factor for poor disease outcome. Our study provides evidence for the multidimensional heterogeneity of t(8;21)AML and may offer new tools for future disease stratification.


Assuntos
Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/patologia , Subpopulações de Linfócitos T/classificação , Subpopulações de Linfócitos T/metabolismo , Adulto , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/metabolismo , Transcriptoma
8.
Scand J Immunol ; 92(5): e12958, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32794199

RESUMO

ANCA-associated vasculitis (AAV) is a group of chronic inflammatory diseases of small- and medium-sized vessels, which are broadly subdivided based on organ manifestations and disease-specific autoantibodies. The so called anti-neutrophil cytoplasmic antibodies (ANCA) mostly target one of the enzymes, proteinase 3 (PR3) or myeloperoxidase (MPO). Accumulating genetic data demonstrates that these two autoantibodies discriminate two distinct disease entities, more so than the clinical subdivision which is mainly criteria-based. Treatment of AAV includes heavy immunosuppression and is guided by which organs that are involved. Generally, patients with PR3-ANCA display higher risk for disease relapse than patients with MPO-ANCA. In this review, we will focus on the autoimmune features of PR3+ AAV and our current understanding of its triggers and the potential translation into clinical practice.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Mieloblastina/imunologia , Peroxidase/imunologia , Animais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/metabolismo , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Cadeias beta de HLA-DP/imunologia , Cadeias beta de HLA-DP/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Modelos Imunológicos , Mieloblastina/metabolismo , Peroxidase/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
9.
Scand J Immunol ; 92(5): e12956, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32767795

RESUMO

In a healthy person, metabolically quiescent T lymphocytes (T cells) circulate between lymph nodes and peripheral tissues in search of antigens. Upon infection, some T cells will encounter cognate antigens followed by proliferation and clonal expansion in a context-dependent manner, to become effector T cells. These events are accompanied by changes in cellular metabolism, known as metabolic reprogramming. The magnitude and variation of metabolic reprogramming are, in addition to antigens, dependent on factors such as nutrients and oxygen to ensure host survival during various diseases. Herein, we describe how metabolic programmes define T cell subset identity and effector functions. In addition, we will discuss how metabolic programs can be modulated and affect T cell activity in health and disease using cancer and autoimmunity as examples.


Assuntos
Autoimunidade/imunologia , Metabolismo Energético/imunologia , Ativação Linfocitária/imunologia , Neoplasias/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Animais , Microambiente Celular/imunologia , Humanos , Modelos Imunológicos , Neoplasias/metabolismo , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/metabolismo
10.
Nat Commun ; 11(1): 3434, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632085

RESUMO

The immune system of patients infected by SARS-CoV-2 is severely impaired. Detailed investigation of T cells and cytokine production in patients affected by COVID-19 pneumonia are urgently required. Here we show that, compared with healthy controls, COVID-19 patients' T cell compartment displays several alterations involving naïve, central memory, effector memory and terminally differentiated cells, as well as regulatory T cells and PD1+CD57+ exhausted T cells. Significant alterations exist also in several lineage-specifying transcription factors and chemokine receptors. Terminally differentiated T cells from patients proliferate less than those from healthy controls, whereas their mitochondria functionality is similar in CD4+ T cells from both groups. Patients display significant increases of proinflammatory or anti-inflammatory cytokines, including T helper type-1 and type-2 cytokines, chemokines and galectins; their lymphocytes produce more tumor necrosis factor (TNF), interferon-γ, interleukin (IL)-2 and IL-17, with the last observation implying that blocking IL-17 could provide a novel therapeutic strategy for COVID-19.


Assuntos
Betacoronavirus/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Senescência Celular , Infecções por Coronavirus/sangue , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Humanos , Memória Imunológica , Itália/epidemiologia , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/patologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Células Th17/imunologia , Células Th17/metabolismo , Células Th17/patologia
11.
JCI Insight ; 5(17)2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32687484

RESUMO

COVID-19-associated morbidity and mortality have been attributed to a pathologic host response. Two divergent hypotheses have been proposed: hyperinflammatory cytokine storm; and failure of host protective immunity that results in unrestrained viral dissemination and organ injury. A key explanation for the inability to address this controversy has been the lack of diagnostic tools to evaluate immune function in COVID-19 infections. ELISpot, a highly sensitive, functional immunoassay, was employed in 27 patients with COVID-19, 51 patients with sepsis, 18 critically ill nonseptic (CINS) patients, and 27 healthy control volunteers to evaluate adaptive and innate immune status by quantitating T cell IFN-É£ and monocyte TFN-α production. Circulating T cell subsets were profoundly reduced in COVID-19 patients. Additionally, stimulated blood mononuclear cells produced less than 40%-50% of the IFN-É£ and TNF-α observed in septic and CINS patients, consistent with markedly impaired immune effector cell function. Approximately 25% of COVID-19 patients had increased IL-6 levels that were not associated with elevations in other canonical proinflammatory cytokines. Collectively, these findings support the hypothesis that COVID-19 suppresses host functional adaptive and innate immunity. Importantly, IL-7 administered ex vivo restored T cell IFN-É£ production in COVID-19 patients. Thus, ELISpot may functionally characterize host immunity in COVID-19 and inform prospective therapies.


Assuntos
Imunidade Adaptativa/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Tolerância Imunológica/imunologia , Imunidade Inata/imunologia , Pneumonia Viral/imunologia , Sepse/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Estudos de Casos e Controles , Estado Terminal , ELISPOT , Feminino , Voluntários Saudáveis , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Pandemias , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
12.
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
13.
Nat Commun ; 11(1): 2859, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503973

RESUMO

Mature double negative (DN) T cells are a population of αß T cells that lack CD4 and CD8 coreceptors and contribute to systemic lupus erythematosus (SLE). The splenic marginal zone macrophages (MZMs) are important for establishing immune tolerance, and loss of their number or function contributes to the progression of SLE. Here we show that loss of MZMs impairs the tolerogenic clearance of apoptotic cells and alters the serum cytokine profile, which in turn provokes the generation of DN T cells from self-reactive CD8+ T cells. Increased Ki67 expression, narrowed TCR V-beta repertoire usage and diluted T-cell receptor excision circles confirm that DN T cells from lupus-prone mice and patients with SLE undergo clonal proliferation and expansion in a self-antigen dependent manner, which supports the shared mechanisms for their generation. Collectively, our results provide a link between the loss of MZMs and the expansion of DN T cells, and indicate possible strategies to prevent the development of SLE.


Assuntos
Autoantígenos/imunologia , Interleucina-17/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Autoantígenos/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Tolerância Imunológica , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Subpopulações de Linfócitos T/metabolismo
14.
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
15.
Nat Immunol ; 21(6): 649-659, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32424359

RESUMO

Efficient generation of germinal center (GC) responses requires directed movement of B cells between distinct microenvironments underpinned by specialized B cell-interacting reticular cells (BRCs). How BRCs are reprogrammed to cater to the developing GC remains unclear, and studying this process is largely hindered by incomplete resolution of the cellular composition of the B cell follicle. Here we used genetic targeting of Cxcl13-expressing cells to define the molecular identity of the BRC landscape. Single-cell transcriptomic analysis revealed that BRC subset specification was predetermined in the primary B cell follicle. Further topological remodeling of light and dark zone follicular dendritic cells required CXCL12-dependent crosstalk with B cells and dictated GC output by retaining B cells in the follicle and steering their interaction with follicular helper T cells. Together, our results reveal that poised BRC-defined microenvironments establish a feed-forward system that determines the efficacy of the GC reaction.


Assuntos
Escuridão , Células Dendríticas Foliculares/imunologia , Células Dendríticas Foliculares/metabolismo , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Imunomodulação/efeitos da radiação , Luz , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Comunicação Celular , Quimiocina CXCL12/metabolismo , Camundongos , Camundongos Transgênicos , Fenótipo , Análise de Célula Única , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
16.
Nat Immunol ; 21(6): 636-648, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32424365

RESUMO

Sepsis and trauma cause inflammation and elevated susceptibility to hospital-acquired pneumonia. As phagocytosis by macrophages plays a critical role in the control of bacteria, we investigated the phagocytic activity of macrophages after resolution of inflammation. After resolution of primary pneumonia, murine alveolar macrophages (AMs) exhibited poor phagocytic capacity for several weeks. These paralyzed AMs developed from resident AMs that underwent an epigenetic program of tolerogenic training. Such adaptation was not induced by direct encounter of the pathogen but by secondary immunosuppressive signals established locally upon resolution of primary infection. Signal-regulatory protein α (SIRPα) played a critical role in the establishment of the microenvironment that induced tolerogenic training. In humans with systemic inflammation, AMs and also circulating monocytes still displayed alterations consistent with reprogramming six months after resolution of inflammation. Antibody blockade of SIRPα restored phagocytosis in monocytes of critically ill patients in vitro, which suggests a potential strategy to prevent hospital-acquired pneumonia.


Assuntos
Epigênese Genética , Inflamação/etiologia , Pulmão/imunologia , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Animais , Biomarcadores , Reprogramação Celular , Citocinas/metabolismo , Humanos , Tolerância Imunológica , Imunofenotipagem , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Pulmão/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos Alveolares/imunologia , Camundongos , Monócitos/imunologia , Monócitos/metabolismo , Fagocitose/imunologia , Pneumonia/etiologia , Pneumonia/metabolismo , Pneumonia/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
17.
Immunity ; 52(5): 825-841.e8, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32396847

RESUMO

CD8+ T cell exhaustion is a major barrier to current anti-cancer immunotherapies. Despite this, the developmental biology of exhausted CD8+ T cells (Tex) remains poorly defined, restraining improvement of strategies aimed at "re-invigorating" Tex cells. Here, we defined a four-cell-stage developmental framework for Tex cells. Two TCF1+ progenitor subsets were identified, one tissue restricted and quiescent and one more blood accessible, that gradually lost TCF1 as it divided and converted to a third intermediate Tex subset. This intermediate subset re-engaged some effector biology and increased upon PD-L1 blockade but ultimately converted into a fourth, terminally exhausted subset. By using transcriptional and epigenetic analyses, we identified the control mechanisms underlying subset transitions and defined a key interplay between TCF1, T-bet, and Tox in the process. These data reveal a four-stage developmental hierarchy for Tex cells and define the molecular, transcriptional, and epigenetic mechanisms that could provide opportunities to improve cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Epigênese Genética/imunologia , Neoplasias/imunologia , Subpopulações de Linfócitos T/imunologia , Transcrição Genética/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Epigênese Genética/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/imunologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/imunologia , Humanos , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Neoplasias/genética , Neoplasias/terapia , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Subpopulações de Linfócitos T/metabolismo , Transcrição Genética/genética
18.
Cancer Sci ; 111(7): 2248-2258, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32426941

RESUMO

Myeloid-derived suppressor cells (MDSCs) play a crucial role in immunosuppression in tumor-bearing hosts. MDSCs express arginase-I and indoleamine 2,3-dioxygenase; they suppress T-cell function by reducing the levels of l-arginine and l-tryptophan, respectively. We examined the anticancer effects of supplementation of these amino acids in CT26 colon carcinoma-bearing mice. Oral supplementation of l-arginine or l-tryptophan (30 mg/mouse) did not affect tumor growth, whereas oral supplementation of d-arginine was lethal. Supplementation of l-arginine showed a tendency to augment the efficacy of cyclophosphamide (CP). CP reduced the proportions of granulocytic MDSCs and increased the proportions of monocytic MDSCs in the spleen and tumor tissues of CT26-bearing mice. l-Arginine supplementation alone did not affect the MDSC subsets. CP treatment tended to reduce the plasma levels of l-arginine in CT26-bearing mice and significantly increased the number of tumor-infiltrating CD8+ T cells. In addition, l-arginine supplementation significantly increased the proportions of tumor peptide-specific CD8+ T cells in draining lymph nodes. Importantly, additional supplementation of l-arginine significantly increased the number of cured mice that were treated with CP and anti-PD-1 antibody. Totally, l-arginine supplementation shows promise for boosting the therapeutic efficacy of chemoimmunotherapy.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Antineoplásicos/farmacologia , Arginina/administração & dosagem , Suplementos Nutricionais , Aminoácidos/sangue , Animais , Antineoplásicos/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclofosfamida/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Citometria de Fluxo , Camundongos , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
19.
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
20.
Immunology ; 160(2): 209-219, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32149403

RESUMO

CD100 is an immune semaphorin constitutively expressed on T-cells. Matrix metalloproteinase (MMP) is an important mediator of membrane-bound CD100 (mCD100) cleavage to generate soluble CD100 (sCD100), which has immunoregulatory activity in immune cell responses. The aim of the study was to investigate the level and role of sCD100 and mCD100 in modulating CD8+ T-cell function in non-small cell lung cancer (NSCLC). sCD100 and MMP-14 levels in the serum and bronchoalveolar lavage fluid (BALF), and mCD100 expression on peripheral and lung-resident CD8+ T-cells were analysed in NSCLC patients. The ability to induce sCD100 and the effect of MMP-14 on mCD100 shedding for the regulation of non-cytolytic and cytolytic functions of CD8+ T-cells were also analysed in direct and indirect contact co-culture systems. NSCLC patients had lower serum sCD100 and higher mCD100 levels on CD8+ T-cells compared with healthy controls. BALF from the tumour site also had decreased sCD100 and increased mCD100 on CD8+ T-cells compared with the non-tumour site. Recombinant CD100 stimulation enhanced non-cytolytic and cytolytic functions of CD8+ T-cells from NSCLC patients, whereas blockade of CD100 receptor CD72 attenuated CD8+ T-cell activity. NSCLC patients had lower MMP-14 in the serum and in BALF from the tumour site. Recombinant MMP-14 mediated mCD100 shedding from CD8+ T-cell membrane, and led to promotion of CD8+ T-cell response in NSCLC patients. Overall, decreased MMP-14 resulted in insufficient CD100 shedding, leading to suppression of peripheral and lung-resident CD8+ T-cell activity in NSCLC.


Assuntos
Antígenos CD/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/imunologia , Metaloproteinase 14 da Matriz/metabolismo , Semaforinas/metabolismo , Adulto , Idoso , Antígenos CD/sangue , Líquido da Lavagem Broncoalveolar/química , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Técnicas de Cocultura , Feminino , Humanos , Pulmão/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Ativação Linfocitária , Masculino , Metaloproteinase 14 da Matriz/sangue , Pessoa de Meia-Idade , Cultura Primária de Células , Proteínas Recombinantes/metabolismo , Semaforinas/sangue , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Evasão Tumoral , Microambiente Tumoral/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA