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1.
Sci Immunol ; 6(61)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210785

RESUMO

A central feature of the SARS-CoV-2 pandemic is that some individuals become severely ill or die, whereas others have only a mild disease course or are asymptomatic. Here we report development of an improved multimeric αß T cell staining reagent platform, with each maxi-ferritin "spheromer" displaying 12 peptide-MHC complexes. Spheromers stain specific T cells more efficiently than peptide-MHC tetramers and capture a broader portion of the sequence repertoire for a given peptide-MHC. Analyzing the response in unexposed individuals, we find that T cells recognizing peptides conserved amongst coronaviruses are more abundant and tend to have a "memory" phenotype, compared to those unique to SARS-CoV-2. Significantly, CD8+ T cells with these conserved specificities are much more abundant in COVID-19 patients with mild disease versus those with a more severe illness, suggesting a protective role.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Epitopos de Linfócito T/imunologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Linfócitos T CD8-Positivos/patologia , COVID-19/patologia , Feminino , Humanos , Masculino
2.
Cell Commun Signal ; 19(1): 73, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238338

RESUMO

BACKGROUND: The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has become an ongoing pandemic. Understanding the respiratory immune microenvironment which is composed of multiple cell types, together with cell communication based on ligand-receptor interactions is important for developing vaccines, probing COVID-19 pathogenesis, and improving pandemic control measures. METHODS: A total of 102 consecutive hospitalized patients with confirmed COVID-19 were enrolled in this study. Clinical information, routine laboratory tests, and flow cytometry analysis data with different conditions were collected and assessed for predictive value in COVID-19 patients. Next, we analyzed public single-cell RNA-sequencing (scRNA-seq) data from bronchoalveolar lavage fluid, which offers the closest available view of immune cell heterogeneity as encountered in patients with varying severity of COVID-19. A weighting algorithm was used to calculate ligand-receptor interactions, revealing the communication potentially associated with outcomes across cell types. Finally, serum cytokines including IL6, IL1ß, IL10, CXCL10, TNFα, GALECTIN-1, and IGF1 derived from patients were measured. RESULTS: Of the 102 COVID-19 patients, 42 cases (41.2%) were categorized as severe. Multivariate logistic regression analysis demonstrated that AST, D-dimer, BUN, and WBC were considered as independent risk factors for the severity of COVID-19. T cell numbers including total T cells, CD4+ and CD8+ T cells in the severe disease group were significantly lower than those in the moderate disease group. The risk model containing the above mentioned inflammatory damage parameters, and the counts of T cells, with AUROCs ranged from 0.78 to 0.87. To investigate the molecular mechanism at the cellular level, we analyzed the published scRNA-seq data and found that macrophages displayed specific functional diversity after SARS-Cov-2 infection, and the metabolic pathway activities in the identified macrophage subtypes were influenced by hypoxia status. Importantly, we described ligand-receptor interactions that are related to COVID-19 serverity involving macrophages and T cell subsets by communication analysis. CONCLUSIONS: Our study showed that macrophages driving ligand-receptor crosstalk contributed to the reduction and exhaustion of CD8+ T cells. The identified crucial cytokine panel, including IL6, IL1ß, IL10, CXCL10, IGF1, and GALECTIN-1, may offer the selective targets to improve the efficacy of COVID-19 therapy. TRIAL REGISTRATION: This is a retrospective observational study without a trial registration number. Video Abstract.


Assuntos
COVID-19/imunologia , COVID-19/patologia , Comunicação Celular , Macrófagos/imunologia , Análise de Célula Única , Idoso , Líquido da Lavagem Broncoalveolar/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , COVID-19/epidemiologia , COVID-19/fisiopatologia , China/epidemiologia , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Receptores de Citocinas , Estudos Retrospectivos , Análise de Sequência de RNA , Índice de Gravidade de Doença
3.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070750

RESUMO

The immune system is a fine modulator of the tumor biology supporting or inhibiting its progression, growth, invasion and conveys the pharmacological treatment effect. Tumors, on their side, have developed escaping mechanisms from the immune system action ranging from the direct secretion of biochemical signals to an indirect reaction, in which the cellular actors of the tumor microenvironment (TME) collaborate to mechanically condition the extracellular matrix (ECM) making it inhospitable to immune cells. TME is composed of several cell lines besides cancer cells, including tumor-associated macrophages, cancer-associated fibroblasts, CD4+ and CD8+ lymphocytes, and innate immunity cells. These populations interface with each other to prepare a conservative response, capable of evading the defense mechanisms implemented by the host's immune system. The presence or absence, in particular, of cytotoxic CD8+ cells in the vicinity of the main tumor mass, is able to predict, respectively, the success or failure of drug therapy. Among various mechanisms of immunescaping, in this study, we characterized the modulation of the phenotypic profile of CD4+ and CD8+ cells in resting and activated states, in response to the mechanical pressure exerted by a three-dimensional in vitro system, able to recapitulate the rheological and stiffness properties of the tumor ECM.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Matriz Extracelular/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Evasão Tumoral , Microambiente Tumoral/imunologia , 5'-Nucleotidase/genética , 5'-Nucleotidase/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Técnicas de Cultura de Células , Módulo de Elasticidade , Matriz Extracelular/química , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Humanos , Hidrogéis/química , Interferon gama/genética , Interferon gama/imunologia , Ativação Linfocitária , Mecanotransdução Celular , Modelos Biológicos , NF-kappa B/genética , NF-kappa B/imunologia , Fenótipo , Cultura Primária de Células , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Reologia , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/imunologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/genética , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/patologia
5.
Nat Commun ; 12(1): 2782, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33986293

RESUMO

Chronic stimulation of CD8+ T cells triggers exhaustion, a distinct differentiation state with diminished effector function. Exhausted cells exist in multiple differentiation states, from stem-like progenitors that are the key mediators of the response to checkpoint blockade, through to terminally exhausted cells. Due to its clinical relevance, there is substantial interest in defining the pathways that control differentiation and maintenance of these subsets. Here, we show that chronic antigen induces the anergy-associated transcription factor EGR2 selectively within progenitor exhausted cells in both chronic LCMV and tumours. EGR2 enables terminal exhaustion and stabilizes the exhausted transcriptional state by both direct EGR2-dependent control of key exhaustion-associated genes, and indirect maintenance of the exhausted epigenetic state. We show that EGR2 is a regulator of exhaustion that epigenetically and transcriptionally maintains the differentiation competency of progenitor exhausted cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Anergia Clonal/imunologia , Proteína 2 de Resposta de Crescimento Precoce/metabolismo , Linfopoese/fisiologia , Animais , Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Proteína 2 de Resposta de Crescimento Precoce/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
6.
Nat Commun ; 12(1): 2593, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972535

RESUMO

The COVID-19 pandemic caused by SARS-CoV-2 is a continuous challenge worldwide, and there is an urgent need to map the landscape of immunogenic and immunodominant epitopes recognized by CD8+ T cells. Here, we analyze samples from 31 patients with COVID-19 for CD8+ T cell recognition of 500 peptide-HLA class I complexes, restricted by 10 common HLA alleles. We identify 18 CD8+ T cell recognized SARS-CoV-2 epitopes, including an epitope with immunodominant features derived from ORF1ab and restricted by HLA-A*01:01. In-depth characterization of SARS-CoV-2-specific CD8+ T cell responses of patients with acute critical and severe disease reveals high expression of NKG2A, lack of cytokine production and a gene expression profile inhibiting T cell re-activation and migration while sustaining survival. SARS-CoV-2-specific CD8+ T cell responses are detectable up to 5 months after recovery from critical and severe disease, and these responses convert from dysfunctional effector to functional memory CD8+ T cells during convalescence.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Epitopos Imunodominantes/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Linfócitos T CD8-Positivos/patologia , COVID-19/patologia , Epitopos de Linfócito T/imunologia , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Epitopos Imunodominantes/química , Memória Imunológica , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Poliproteínas/imunologia , Proteínas Virais/imunologia
7.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803482

RESUMO

Alzheimer's disease (AD) is the most common form of dementia. In particular, neuroinflammation, mediated by microglia cells but also through CD8+ T-cells, actively contributes to disease pathology. Leukotrienes are involved in neuroinflammation and in the pathological hallmarks of AD. In consequence, leukotriene signaling-more specifically, the leukotriene receptors-has been recognized as a potential drug target to ameliorate AD pathology. Here, we analyzed the effects of the leukotriene receptor antagonist montelukast (MTK) on hippocampal gene expression in 5xFAD mice, a commonly used transgenic AD mouse model. We identified glial activation and neuroinflammation as the main pathways modulated by MTK. The treatment increased the number of Tmem119+ microglia and downregulated genes related to AD-associated microglia and to lipid droplet-accumulating microglia, suggesting that the MTK treatment targets and modulates microglia phenotypes in the disease model compared to the vehicle. MTK treatment further reduced infiltration of CD8+T-cells into the brain parenchyma. Finally, MTK treatment resulted in improved cognitive functions. In summary, we provide a proof of concept for MTK to be a potential drug candidate for AD and provide novel modes of action via modulation of microglia and CD8+ T-cells. Of note, 5xFAD females showed a more severe pathology, and in consequence, MTK treatment had a more pronounced effect in the females compared to the males. The effects on neuroinflammation, i.e., microglia and CD8+ T-cells, as well as the effects on cognitive outcome, were dose-dependent, therefore arguing for the use of higher doses of MTK in AD clinical trials compared to the approved asthma dose.


Assuntos
Acetatos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Encéfalo/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Cognição/efeitos dos fármacos , Ciclopropanos/farmacologia , Antagonistas de Leucotrienos/farmacologia , Quinolinas/farmacologia , Sulfetos/farmacologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Linfócitos T CD8-Positivos/patologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Transgênicos
8.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807704

RESUMO

Alopecia areata (AA) is regarded as a tissue-specific and cell-mediated autoimmune disorder. Regarding the cytokine balance, AA has been considered a type 1 inflammatory disease. On the other hand, AA often complicates atopic dermatitis (AD) and AD is regarded as type 2 inflammatory disease. However, the immunological aspects of AA in relation to AD are still poorly understood. Therefore, we aim to clarify the immunological properties of AD-associated AA. In this study, we performed comparative analysis of the expression of intracytoplasmic cytokines (IFN-γ, IL-4, and IL-13), chemokine receptors (CXCR3 and CCR4) in peripheral blood which were taken from healthy controls, non-atopic AA patients, AA patients with extrinsic AD, and AA patients with intrinsic AD by flowcytometric analysis. We also compared the scalp skin samples taken from AA patients with extrinsic AD before and after treatment with dupilumab. In non-atopic AA patients, the ratios of CD4+IFN-γ+ cells to CD4+IL-4+ cells and CD4+IFN-γ+ cells to CD4+IL-13+ cells were higher than those in AA patients with extrinsic AD. Meanwhile, the ratio of CD8+IFN-γ+ cells to CD8+IL-13+ cells was significantly higher in the non-atopic AA than in the healthy controls. In AA patients with extrinsic AD, the skin AA lesion showed dense infiltration of not only CXCR3+ cells but also CCR4+ cells around hair bulb before dupilumab treatment. However, after the treatment, the number of CXCR3+ cells had no remarkable change while the number of CCR4+ cells significantly decreased. These results indicate that the immunological condition of AA may be different between atopic and non-atopic patients and between extrinsic and intrinsic AD patients. Our study provides an important notion that type 2 immunity may participate in the development of AA in extrinsic AD patients. It may be considered that the immunological state of non-atopic AA is different from that of atopic AA.


Assuntos
Alopecia em Áreas/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Dermatite Atópica/imunologia , Adulto , Alopecia em Áreas/tratamento farmacológico , Alopecia em Áreas/patologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Citocinas/imunologia , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Receptores CCR4/imunologia , Receptores CXCR3/imunologia , Adulto Jovem
9.
Front Immunol ; 12: 653974, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897702

RESUMO

This study discusses substantive advances in T cell proliferation analysis, with the aim to provoke a re-evaluation of the generally-held view that Ki-67 is a reliable proliferation marker per se, and to offer a more sensitive and effective method for T cell cycle analysis, with informative examples in mouse and human settings. We summarize recent experimental work from our labs showing that, by Ki-67/DNA dual staining and refined flow cytometric methods, we were able to identify T cells in the S-G2/M phases of the cell-cycle in the peripheral blood (collectively termed "T Double S" for T cells in S-phase in Sanguine: in short "TDS" cells). Without our refinement, such cells may be excluded from conventional lymphocyte analyses. Specifically, we analyzed clonal expansion of antigen-specific CD8 T cells in vaccinated mice, and demonstrated the potential of TDS cells to reflect immune dynamics in human blood samples from healthy donors, and patients with type 1 diabetes, infectious mononucleosis, and COVID-19. The Ki-67/DNA dual staining, or TDS assay, provides a reliable approach by which human peripheral blood can be used to reflect the dynamics of human lymphocytes, rather than providing mere steady-state phenotypic snapshots. The method does not require highly sophisticated "-omics" capabilities, so it should be widely-applicable to health care in diverse settings. Furthermore, our results argue that the TDS assay can provide a window on immune dynamics in extra-lymphoid tissues, a long-sought potential of peripheral blood monitoring, for example in relation to organ-specific autoimmune diseases and infections, and cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Ciclo Celular/imunologia , Diabetes Mellitus Tipo 1/imunologia , Antígeno Ki-67/imunologia , Neoplasias/imunologia , SARS-CoV-2/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , COVID-19/patologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/uso terapêutico , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/terapia , Humanos , Camundongos , Neoplasias/patologia , Neoplasias/terapia
10.
Molecules ; 26(7)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33805933

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory disease mainly affecting the synovial joints. A highly potent antagonist of C-C chemokine receptor 5 (CCR5), maraviroc (MVC), plays an essential role in treating several infectious diseases but has not yet been evaluated for its potential effects on RA development. This study focused on evaluating the therapeutic potential of MVC on collagen-induced arthritis (CIA) in DBA/1J mice. Following CIA induction, animals were treated intraperitoneally with MVC (50 mg/kg) daily from day 21 until day 35 and evaluated for clinical score and histopathological changes in arthritic inflammation. We further investigated the effect of MVC on Th9 (IL-9, IRF-4, and GATA3) and Th17 (IL-21R, IL-17A, and RORγT) cells, TNF-α, and RANTES in CD8+ T cells in the spleen using flow cytometry. We also assessed the effect of MVC on mRNA and protein levels of IL-9, IL-17A, RORγT, and GATA3 in knee tissues using RT-PCR and western blot analysis. MVC treatment in CIA mice attenuated the clinical and histological severity of inflammatory arthritis, and it substantially decreased IL-9, IRF4, IL-21R, IL-17A, RORγT, TNF-α, and RANTES production but increased GATA3 production in CD8+ T cells. We further observed that MVC treatment decreased IL-9, IL-17A, and RORγt mRNA and protein levels and increased those of GATA3. This study elucidates the capacity of MVC to ameliorate the clinical and histological signs of CIA by reducing pro-inflammatory responses, suggesting that MVC may have novel therapeutic uses in the treatment of RA.


Assuntos
Artrite Experimental/tratamento farmacológico , Maraviroc/farmacologia , Receptores CCR5/imunologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Citocinas/imunologia , Fator de Transcrição GATA3/imunologia , Masculino , Camundongos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Células Th17/imunologia , Células Th17/patologia , Receptor Toll-Like 9/imunologia
11.
Mol Cell ; 81(11): 2477-2493.e10, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33891860

RESUMO

CD8 T cells play an essential role in defense against viral and bacterial infections and in tumor immunity. Deciphering T cell loss of functionality is complicated by the conspicuous heterogeneity of CD8 T cell states described across experimental and clinical settings. By carrying out a unified analysis of over 300 assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) experiments from 12 studies of CD8 T cells in cancer and infection, we defined a shared differentiation trajectory toward dysfunction and its underlying transcriptional drivers and revealed a universal early bifurcation of functional and dysfunctional T cell states across models. Experimental dissection of acute and chronic viral infection using single-cell ATAC (scATAC)-seq and allele-specific single-cell RNA (scRNA)-seq identified state-specific drivers and captured the emergence of similar TCF1+ progenitor-like populations at an early branch point, at which functional and dysfunctional T cells diverge. Our atlas of CD8 T cell states will facilitate mechanistic studies of T cell immunity and translational efforts.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Epigênese Genética/imunologia , Imunidade Celular , Coriomeningite Linfocítica/genética , Neoplasias/genética , Fatores de Transcrição/genética , Doença Aguda , Atlas como Assunto , Linfócitos T CD8-Positivos/classificação , Linfócitos T CD8-Positivos/patologia , Cromatina/química , Cromatina/imunologia , Doença Crônica , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Ativação Linfocitária , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/patologia , Vírus da Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/patogenicidade , Neoplasias/imunologia , Neoplasias/patologia , Análise de Componente Principal , Análise de Célula Única , Fatores de Transcrição/classificação , Fatores de Transcrição/imunologia , Transcrição Genética , Transposases/genética , Transposases/metabolismo
12.
Isr Med Assoc J ; 23(3): 153-159, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33734627

RESUMO

BACKGROUND: Immune cell counts in blood in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection may be useful prognostic biomarkers of disease severity, mortality, and response to treatment. OBJECTIVES: To analyze sub-populations of lymphocytes at hospital admission in survivors and deceased from severe pneumonia due to coronavirus disease-2019 (COVID-19). METHODS: We conducted a cross-sectional study of healthcare workers confirmed with SARS-CoV-2 in convalescents (control group) and healthy controls (HC) diagnosed with severe COVID-19. Serum samples were taken at hospital admission and after recovery. Serum samples ≥ 25 days after onset of symptoms were analyzed for lymphocyte subpopulations through flow cytometry. Descriptive statistics, Kruskall-Wallis test, receiver operating characteristic curve, calculation of sensitivity, specificity, predictive values, and Kaplan-Meier analysis were performed. RESULTS: We included 337 patients: 120 HC, 127 convalescents, and 90 severe COVID-19 disease patients (50 survivors, 40 deceased). For T cells, total lymphocytes ≥ 800/µL, CD3+ ≥ 400/µL, CD4+ ≥ 180/µL, CD8+ ≥ 150/µL, B cells CD19+ ≥ 80/µL, and NK ≥ 34/µL subsets were associated with survival in severe COVID-19 disease patients. All subtypes of lymphocytes had higher concentrations in survivors than deceased, but similar between HC and convalescents. Leukocytes ≥ 10.150/µL or neutrophils ≥ 10,000/µL were associated with increased mortality. The neutrophil-to-lymphocyte ratio (NLR) ≥ 8.5 increased the probability of death in severe COVID-19 (odds ratio 11.68). CONCLUSIONS: Total lymphocytes; NLR; and levels of CD3+, CD4+, CD8+, and NK cells are useful as biomarkers of survival or mortality in severe COVID-19 disease and commonly reach normal levels in convalescents.


Assuntos
Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , COVID-19 , Linfopenia , Neutrófilos/patologia , Biomarcadores/sangue , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/mortalidade , COVID-19/terapia , Correlação de Dados , Estudos Transversais , Feminino , Humanos , Estimativa de Kaplan-Meier , Células Matadoras Naturais/patologia , Contagem de Leucócitos/métodos , Linfopenia/sangue , Linfopenia/diagnóstico , Linfopenia/etiologia , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Mortalidade , Valor Preditivo dos Testes , Avaliação de Sintomas/métodos
13.
Signal Transduct Target Ther ; 6(1): 126, 2021 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-33758164

RESUMO

The efficient induction and long-term persistence of pathogen-specific memory CD8 T cells are pivotal to rapidly curb the reinfection. Recent studies indicated that long-noncoding RNAs expression is highly cell- and stage-specific during T cell development and differentiation, suggesting their potential roles in T cell programs. However, the key lncRNAs playing crucial roles in memory CD8 T cell establishment remain to be clarified. Through CD8 T cell subsets profiling of lncRNAs, this study found a key lncRNA-Snhg1 with the conserved naivehi-effectorlo-memoryhi expression pattern in CD8 T cells of both mice and human, that can promote memory formation while impeding effector CD8 in acute viral infection. Further, Snhg1 was found interacting with the conserved vesicle trafficking protein Vps13D to promote IL-7Rα membrane location specifically. With the deep mechanism probing, the results show Snhg1-Vps13D regulated IL-7 signaling with its dual effects in memory CD8 generation, which not just because of the sustaining role of STAT5-BCL-2 axis for memory survival, but more through the STAT3-TCF1-Blimp1 axis for transcriptional launch program of memory differentiation. Moreover, we performed further study with finding a similar high-low-high expression pattern of human SNHG1/VPS13D/IL7R/TCF7 in CD8 T cell subsets from PBMC samples of the convalescent COVID-19 patients. The central role of Snhg1-Vps13D-IL-7R-TCF1 axis in memory CD8 establishment makes it a potential target for improving the vaccination effects to control the ongoing pandemic.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Interleucina-7/imunologia , Proteínas/imunologia , RNA Longo não Codificante/imunologia , SARS-CoV-2/imunologia , Vesículas Secretórias/imunologia , Transdução de Sinais/imunologia , Animais , Transporte Biológico Ativo , Linfócitos T CD8-Positivos/patologia , COVID-19/patologia , Humanos , Memória Imunológica , Camundongos , Vesículas Secretórias/patologia
14.
Front Endocrinol (Lausanne) ; 12: 596518, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33776910

RESUMO

Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04365634. Context: Diabetes mellitus was associated with increased severity and mortality of disease in COVID-19 pneumonia. So far the effect of type 2 diabetes (T2DM) or hyperglycemia on the immune system among COVID-19 disease has remained unclear. Objective: We aim to explore the clinical and immunological features of type 2 diabetes mellitus (T2DM) among COVID-19 patients. Design and Methods: In this retrospective study, the clinical and immunological characteristics of 306 hospitalized confirmed COVID-19 patients (including 129 diabetic and 177 non-diabetic patients) were analyzed. The serum concentrations of laboratory parameters including cytokines and numbers of immune cells were measured and compared between diabetic and non-diabetic groups. Results: Compared with non-diabetic group, diabetic cases more frequently had lymphopenia and hyperglycemia, with higher levels of urea nitrogen, myoglobin, D-dimer and ferritin. Diabetic cases indicated the obviously elevated mortality and the higher levels of cytokines IL-2R, IL-6, IL-8, IL-10, and TNF-α, as well as the distinctly reduced Th1/Th2 cytokines ratios compared with non-diabetic cases. The longitudinal assays showed that compared to that at week 1, the levels of IL-6 and IL-8 were significantly elevated at week 2 after admission in non-survivors of diabetic cases, whereas there were greatly reductions from week 1 to week 2 in survivors of diabetic cases. Compared with survival diabetic patients, non-survival diabetic cases displayed distinct higher serum concentrations of IL-2R, IL-6, IL-8, IL-10, TNF-α, and lower Th1/Th2 cytokines ratios at week 2. Samples from a subset of participants were evaluated by flow cytometry for the immune cells. The counts of peripheral total T lymphocytes, CD4+ T cells, CD8+ T cells and NK cells were markedly lower in diabetic cases than in non-diabetic cases. The non-survivors showed the markedly declined counts of CD8+ T cells and NK cells than survivors. Conclusion: The elevated cytokines, imbalance of Th1/Th2 cytokines ratios and reduced of peripheral numbers of CD8+ T cells and NK cells might contribute to the pathogenic mechanisms of high mortality of COVID-19 patients with T2DM.


Assuntos
COVID-19/imunologia , Diabetes Mellitus Tipo 2/imunologia , Adulto , Idoso , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , COVID-19/sangue , COVID-19/complicações , COVID-19/mortalidade , China/epidemiologia , Citocinas/análise , Citocinas/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/mortalidade , Feminino , Humanos , Hiperglicemia/sangue , Hiperglicemia/complicações , Hiperglicemia/imunologia , Hiperglicemia/mortalidade , Sistema Imunitário/metabolismo , Sistema Imunitário/patologia , Células Matadoras Naturais/patologia , Contagem de Linfócitos , Linfopenia/sangue , Linfopenia/complicações , Linfopenia/imunologia , Linfopenia/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Células Th1/patologia , Células Th2/patologia
15.
Nat Commun ; 12(1): 1483, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674611

RESUMO

Acute myocardial infarction is a common condition responsible for heart failure and sudden death. Here, we show that following acute myocardial infarction in mice, CD8+ T lymphocytes are recruited and activated in the ischemic heart tissue and release Granzyme B, leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8+ T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8+ T cells. The protective effect of CD8 depletion on heart function is confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of GRANZYME B in patients with acute myocardial infarction predict increased risk of death at 1-year follow-up. Our work unravels a deleterious role of CD8+ T lymphocytes following acute ischemia, and suggests potential therapeutic strategies targeting pathogenic CD8+ T lymphocytes in the setting of acute myocardial infarction.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Granzimas/genética , Granzimas/metabolismo , Coração/fisiopatologia , Remodelação Ventricular/fisiologia , Animais , Apoptose , Linfócitos T CD8-Positivos/patologia , Modelos Animais de Doenças , Feminino , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Proteínas de Homeodomínio/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/metabolismo , Miocárdio/patologia , Suínos , Transcriptoma
16.
Signal Transduct Target Ther ; 6(1): 113, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33686064

RESUMO

The adaptive immunity that protects patients from coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not well characterized. In particular, the asymptomatic patients have been found to induce weak and transient SARS-CoV-2 antibody responses, but the underlying mechanisms remain unknown; meanwhile, the protective immunity that guide the recovery of these asymptomatic patients is elusive. Here, we characterized SARS-CoV-2-specific B-cell and T-cell responses in 10 asymptomatic patients and 64 patients with other disease severity (mild, n = 10, moderate, n = 32, severe, n = 12) and found that asymptomatic or mild symptomatic patients failed to mount virus-specific germinal center (GC) B cell responses that result in robust and prolonged humoral immunity, assessed by GC response indicators including follicular helper T (TFH) cell and memory B cell responses as well as serum CXCL13 levels. Alternatively, these patients mounted potent virus-specific TH1 and CD8+ T cell responses. In sharp contrast, patients of moderate or severe disease induced vigorous virus-specific GC B cell responses and associated TFH responses; however, the virus-specific TH1 and CD8+ T cells were minimally induced in these patients. These results, therefore, uncovered the protective immunity in asymptomatic patients and also revealed the strikingly dichotomous and incomplete humoral and cellular immune responses in COVID-19 patients with different disease severity, providing important insights into rational design of effective COVID-19 vaccines.


Assuntos
Imunidade Adaptativa , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Células Th1/imunologia , Adulto , Linfócitos B/patologia , Linfócitos T CD8-Positivos/patologia , COVID-19/patologia , Feminino , Humanos , Masculino , Índice de Gravidade de Doença , Células Th1/patologia
17.
Biomed Res Int ; 2021: 9409836, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33688504

RESUMO

Background: Hepatocellular carcinoma (HCC), one of the most common primary malignancies, is theoretically an epitope candidate for immune checkpoint inhibitors, and therefore, the identification of HCC biomarkers is important. Structure-specific recognition protein 1 (SSRP1) is involved in almost all chromatin-related processes, including DNA replication, repair, and transcription. However, its role in HCC remains to be elucidated. Methods: This study investigated the expression of SSRP1 in HCCDB, Oncomine, HPA, and other databases. The prognostic value of SSRP1 in HCC and its relationship with clinical characteristics were then explored using Kaplan-Meier plotter. At the same time, SSRP1 coexpression genes were explored and functionally annotated in the LinkedOmics database. Finally, the correlation between the SSRP1 expression and HCC immune cell infiltration was explored in TIMER and online single-cell sequencing database. Results: Significantly elevated transcriptional and proteomic SSRP1 expressions were found in HCC. Increased SSRP1 mRNA expression was significantly correlated with relevant clinicopathological parameters such as immune cells. Notably, the SSRP1 expression was positively correlated with the infiltration levels of Treg and CD8+ T cells, especially exhausted CD8+ T cells. Interestingly, the SSRP1 expression was higher in both tumor Treg and exhausted CD8+ T cells than in adjacent tissues. Conclusion: SSRP1, as a new prognostic marker for HCC, promotes HCC development by influencing the infiltration of depleted CD8+ T cells and may influence the effect of immunotherapy.


Assuntos
Biomarcadores Tumorais/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Hepatocelular , Proteínas de Ligação a DNA/imunologia , Proteínas de Grupo de Alta Mobilidade/imunologia , Neoplasias Hepáticas , Linfócitos do Interstício Tumoral/imunologia , Proteínas de Neoplasias/imunologia , Fatores de Elongação da Transcrição/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Taxa de Sobrevida
18.
Cancer Sci ; 112(5): 1746-1757, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33735485

RESUMO

Several studies have reported that tissue-resident memory T cells (TRM cells) or tertiary lymphoid structures (TLSs) are associated with a good prognosis. The aim of this study was to clarify the association of TRM cells and TLSs in the tumor immune microenvironment in gastric cancer (GC). We performed immunohistochemical and immunofluorescence staining to detect the presence of CD103+ T cells and to assess the association between CD103+ T cells and TLSs. CD103+ T cells were observed in the tumor epithelium accompanied by CD8+ T cells and were associated with a better prognosis in GC. Furthermore, CD103+ T cells were located around TLSs, and patients with CD103high had more rich TLSs. Patients who had both CD103high cells and who were TLS-rich had a better prognosis than patients with CD103low cells and who were TLS-poor. Moreover, for patients who received PD-1 blockade therapy, CD103high and TLS-rich predicted a good response. Flow cytometry was performed to confirm the characteristics of CD103+ CD8+ T cells and showed that CD103+ CD8+ T cells in GC expressed higher levels of PD-1, granzyme B, and interferon-γ than CD103- CD8+ T cells. Our results suggested that CD103+ CD8+ cells in GC are correlated with TLSs, resulting in enhanced antitumor immunity in GC.


Assuntos
Antígenos CD , Linfócitos T CD8-Positivos/imunologia , Cadeias alfa de Integrinas , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Gástricas/imunologia , Estruturas Linfoides Terciárias/imunologia , Microambiente Tumoral/imunologia , Idoso , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Feminino , Granzimas/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunidade Celular , Interferon gama/metabolismo , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Curva ROC , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Estruturas Linfoides Terciárias/metabolismo
19.
Eur J Immunol ; 51(6): 1535-1538, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33768543

RESUMO

Despite high levels of CXCR3 ligands in mechanically ventilated COVID-19 patients, BALF CD8 T cells were not enriched in CXCR3+ cells but rather CCR6+ , likely due to high CCL20 levels in BALF, and had very high PD-1 expression. In mechanically ventilated, but not ward, patients Th-1 immunity is impaired. ​.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Quimiocina CCL20/imunologia , Pulmão/imunologia , Receptores CCR6/imunologia , Respiração Artificial , SARS-CoV-2/imunologia , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/patologia , COVID-19/patologia , COVID-19/terapia , Feminino , Humanos , Pulmão/patologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade
20.
Eur J Immunol ; 51(6): 1436-1448, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33784417

RESUMO

COVID-19 is a life-threatening disease leading to bilateral pneumonia and respiratory failure. The underlying reasons why a smaller percentage of patients present with severe pulmonary symptoms whereas the majority is only mildly affected are to date not well understood. Comparing the immunological phenotype in healthy donors and patients with mild versus severe COVID-19 shows that in COVID-19 patients, NK-/B-cell activation and proliferation are enhanced independent of severity. As an important precondition for effective antibody responses, T-follicular helper cells and antibody secreting cells are increased both in patients with mild and severe SARS-CoV-2 infection. Beyond this, T cells in COVID-19 patients exhibit a stronger activation profile with differentiation toward effector cell phenotypes. Importantly, when looking at the rates of pulmonary complications in COVID-19 patients, the chemokine receptor CCR4 is higher expressed by both CD4 and CD8 T cells of patients with severe COVID-19. This raises the hypothesis that CCR4 upregulation on T cells in the pathogenesis of COVID-19 promotes stronger T-cell attraction to the lungs leading to increased immune activation with presumably higher pulmonary toxicity. Our study contributes significantly to the understanding of the immunological changes during COVID-19, as new therapeutic agents, preferentially targeting the immune system, are highly warranted.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Pulmão/imunologia , Ativação Linfocitária , Receptores CCR4/imunologia , SARS-CoV-2/imunologia , Regulação para Cima/imunologia , Adulto , Linfócitos T CD8-Positivos/patologia , COVID-19/patologia , Feminino , Humanos , Pulmão/patologia , Pulmão/virologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
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