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1.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34208904

RESUMO

Neonates are at an increased risk of an infectious disease. This is consistent with an increased abundance of myeloid-derived suppressor cells (MDSCs) compared with older children and adults. Using a murine model of neonatal bacterial sepsis, we demonstrate that MDSCs modulate their activity during an infection to enhance immune suppressive functions. A gene expression analysis shows that MDSCs increased NOS2, Arg-1 and IL-27p28 expression in vitro and in vivo in response to Escherichia coli O1:K1:H7 and this is regulated at the level of the gene expression. Changes in the effector gene expression are consistent with increased enzymatic activity and cytokine secretion. The neonatal MDSCs express toll-like receptor (TLR) 2, 4 and 5 capable of recognizing pathogen-associated molecular patterns (PAMPS) on E. coli. However, a variable level of effector expression was achieved in response to LPS, peptidoglycan or flagellin. Individual bacterial PAMPs did not stimulate the expression of Arg-l and IL-27p28 equivalently to E. coli. However, the upregulation of NOS2 was achieved in response to LPS, peptidoglycan and flagella. The increased immune suppressive profile translated to an enhanced suppression of CD4+ T cell proliferation. Collectively, these findings increase our understanding of the dynamic nature of MDSC activity and suggest that these cells abundant in early life can acquire activity during an infection that suppresses protective immunity.


Assuntos
Infecções por Escherichia coli/imunologia , Escherichia coli/patogenicidade , Células Supressoras Mieloides/metabolismo , Sepse Neonatal/microbiologia , Animais , Animais Recém-Nascidos , Linfócitos T CD4-Positivos/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Recém-Nascido , Camundongos , Sepse Neonatal/genética , Sepse Neonatal/imunologia , Óxido Nítrico Sintase Tipo II/genética , Receptores Toll-Like/genética
2.
Nat Commun ; 12(1): 3754, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145241

RESUMO

Atherosclerosis is a major underlying cause of cardiovascular disease. Previous studies showed that inhibition of the co-stimulatory CD40 ligand (CD40L)-CD40 signaling axis profoundly attenuates atherosclerosis. As CD40L exerts multiple functions depending on the cell-cell interactions involved, we sought to investigate the function of the most relevant CD40L-expressing cell types in atherosclerosis: T cells and platelets. Atherosclerosis-prone mice with a CD40L-deficiency in CD4+ T cells display impaired Th1 polarization, as reflected by reduced interferon-γ production, and smaller atherosclerotic plaques containing fewer T-cells, smaller necrotic cores, an increased number of smooth muscle cells and thicker fibrous caps. Mice with a corresponding CD40-deficiency in CD11c+ dendritic cells phenocopy these findings, suggesting that the T cell-dendritic cell CD40L-CD40 axis is crucial in atherogenesis. Accordingly, sCD40L/sCD40 and interferon-γ concentrations in carotid plaques and plasma are positively correlated in patients with cerebrovascular disease. Platelet-specific deficiency of CD40L does not affect atherogenesis but ameliorates atherothrombosis. Our results establish divergent and cell-specific roles of CD40L-CD40 in atherosclerosis, which has implications for therapeutic strategies targeting this pathway.


Assuntos
Aterosclerose/patologia , Linfócitos T CD4-Positivos/metabolismo , Antígenos CD40/metabolismo , Ligante de CD40/metabolismo , Interferon gama/metabolismo , Placa Aterosclerótica/patologia , Animais , Plaquetas/metabolismo , Linfócitos T CD4-Positivos/citologia , Doenças Cardiovasculares/patologia , Células Dendríticas/imunologia , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/citologia , Transdução de Sinais/fisiologia , Trombose/patologia
3.
Nat Commun ; 12(1): 3933, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34168132

RESUMO

Thymic T cell development and T cell receptor repertoire selection are dependent on essential molecular cues provided by thymic epithelial cells (TEC). TEC development and function are regulated by their epigenetic landscape, in which the repressive H3K27me3 epigenetic marks are catalyzed by polycomb repressive complex 2 (PRC2). Here we show that a TEC-targeted deficiency of PRC2 function results in a hypoplastic thymus with reduced ability to express antigens and select a normal repertoire of T cells. The absence of PRC2 activity reveals a transcriptomically distinct medullary TEC lineage that incompletely off-sets the shortage of canonically-derived medullary TEC whereas cortical TEC numbers remain unchanged. This alternative TEC development is associated with the generation of reduced TCR diversity. Hence, normal PRC2 activity and placement of H3K27me3 marks are required for TEC lineage differentiation and function and, in their absence, the thymus is unable to compensate for the loss of a normal TEC scaffold.


Assuntos
Epigênese Genética , Células Epiteliais/citologia , Complexo Repressor Polycomb 2/genética , Timo/citologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Linhagem da Célula , Células Epiteliais/fisiologia , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Complexo Repressor Polycomb 2/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/citologia , Linfócitos T/fisiologia , Timócitos/citologia , Timócitos/fisiologia , Timo/fisiologia
4.
Nat Commun ; 12(1): 3691, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140527

RESUMO

The HIV-1 accessory proteins Vif, Vpu, and Nef can promote infection by overcoming the inhibitory effects of the host cell restriction factors APOBEC3G, Tetherin, and SERINC5, respectively. However, how the HIV-1 accessory protein Vpr enhances infection in macrophages but not in CD4+ T cells remains elusive. Here, we report that Vpr counteracts lysosomal-associated transmembrane protein 5 (LAPTM5), a potent inhibitor of HIV-1 particle infectivity, to enhance HIV-1 infection in macrophages. LAPTM5 transports HIV-1 envelope glycoproteins to lysosomes for degradation, thereby inhibiting virion infectivity. Vpr counteracts the restrictive effects of LAPTM5 by triggering its degradation via DCAF1. In the absence of Vpr, the silencing of LAPTM5 precisely phenocopied the effect of Vpr on HIV-1 infection. In contrast, Vpr did not enhance HIV-1 infection in the absence of LAPTM5. Moreover, LAPTM5 was highly expressed in macrophages but not in CD4+ T lymphocytes. Re-expressing LAPTM5 reconstituted the Vpr-dependent promotion of HIV-1 infection in primary CD4+ T cells, as observed in macrophages. Herein, we demonstrate the molecular mechanism used by Vpr to overcome LAPTM5 restriction in macrophages, providing a potential strategy for anti-HIV/AIDS therapeutics.


Assuntos
Infecções por HIV/metabolismo , HIV-1/metabolismo , Interações entre Hospedeiro e Microrganismos , Macrófagos/metabolismo , Macrófagos/virologia , Proteínas de Membrana/metabolismo , Produtos do Gene vpr do Vírus da Imunodeficiência Humana/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Inativação Gênica , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/genética , HIV-1/patogenicidade , HIV-2/metabolismo , HIV-2/patogenicidade , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Lisossomos/metabolismo , Proteínas de Membrana/genética , Estabilidade Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Vírus da Imunodeficiência Símia/metabolismo , Vírus da Imunodeficiência Símia/patogenicidade , Ubiquitina-Proteína Ligases/metabolismo , Regulação para Cima , Vírion/metabolismo
5.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073995

RESUMO

Human T-cell leukemia virus type 1 (HTLV-1), the cause of adult T-cell leukemia/lymphoma (ATLL), is a retrovirus, which integrates into the host genome and persistently infects CD4+ T-cells. Virus propagation is stimulated by (1) clonal expansion of infected cells and (2) de novo infection. Viral gene expression is induced by the transactivator protein Tax, which recruits host factors like positive transcription elongation factor b (P-TEFb) to the viral promoter. Since HTLV-1 gene expression is repressed in vivo by viral, cellular, and epigenetic mechanisms in late phases of infection, HTLV-1 avoids an efficient CD8+ cytotoxic T-cell (CTL) response directed against the immunodominant viral Tax antigen. Hence, therapeutic strategies using latency reversing agents (LRAs) sought to transiently activate viral gene expression and antigen presentation of Tax to enhance CTL responses towards HTLV-1, and thus, to expose the latent HTLV-1 reservoir to immune destruction. Here, we review strategies that aimed at enhancing Tax expression and Tax-specific CTL responses to interfere with HTLV-1 latency. Further, we provide an overview of LRAs including (1) histone deacetylase inhibitors (HDACi) and (2) activators of P-TEFb, that have mainly been studied in context of human immunodeficiency virus (HIV), but which may also be powerful in the context of HTLV-1.


Assuntos
Regulação Viral da Expressão Gênica/efeitos dos fármacos , Produtos do Gene tax/imunologia , Produtos do Gene tax/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Leucemia-Linfoma de Células T do Adulto/imunologia , Fator B de Elongação Transcricional Positiva/metabolismo , Latência Viral/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Regulação Viral da Expressão Gênica/genética , Produtos do Gene tax/genética , Inibidores de Histona Desacetilases/uso terapêutico , Histonas/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Humanos , Leucemia-Linfoma de Células T do Adulto/metabolismo , Leucemia-Linfoma de Células T do Adulto/patologia , Leucemia-Linfoma de Células T do Adulto/virologia , Fosforilação , Latência Viral/genética
6.
Medicine (Baltimore) ; 100(22): e26188, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087884

RESUMO

ABSTRACT: EFNA1 is a key gene that is associated with the pathogenesis of several human cancers. However, the prognostic role of EFNA1 in many cancers and the relationship between EFNA1 and tumor-infiltrating lymphocytes in different cancers remain unclear.The expression levels of EFNA1 in 33 types of cancer in the TCGA (The Cancer Genome Atlas) database were collected via the UCSC Xena browser. The clinical data of LGG (low grade glioma) patients were downloaded from the TCGA database. The glioma data from the CGGA (Chinese Glioma Genome Atlas) database were also downloaded to verify the results. Kaplan-Meier and Cox regression analyses were used to investigate the prognostic value of EFNA1 in different cancers using R software. We verified the differential expression of EFNA1 in glioma and normal brain tissue via gene expression profiling interactive analysis. We evaluated the relationship between the expression level of EFNA1 and the clinicopathological features of LGG patients via the Wilcoxon signed-rank test. The immune infiltration levels were evaluated via tumor immune estimation resource (TIMER) and CIBERSORT, and the correlations between EFNA1 and immune cell levels were investigated via TIMER. Finally, we conducted gene set enrichment analysis (GSEA) to explore the potential mechanisms.Data from the TCGA database showed that EFNA1 was differentially expressed in many kinds of cancers when compared with normal tissues. Upregulated EFNA1 expression in esophageal carcinoma (ESCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), and LGG correlated with shorter patient overall survival (OS) times. The Cox regression analysis revealed that the expression of EFNA1 was also a risk factor for the disease-specific survival (DSS) and progression-free interval (PFI) of LGG patients. The multiple Cox regression analysis revealed that EFNA1 was an independent prognostic factor for LGG patients. In addition, EFNA1 expression was increased in the WHO grade III group and the 1p19q non-codeletion group. Moreover, EFNA1 expression was positively correlated with the levels of infiltrating CD4+ T cells, myeloid dendritic cells and neutrophils in LGG. GSEA suggested that several GO and kyoto encyclopedia of genes and genomes (KEGG) items associated with nervous system function and apoptotic pathway were significantly enriched in the EFNA1-low and EFNA1-high expression phenotypes.EFNA1 may play a pivotal role in the development of LGG and may serve as a potential marker for LGG prognosis and therapy.


Assuntos
Neoplasias Encefálicas/patologia , Efrina-A1/genética , Perfilação da Expressão Gênica/métodos , Glioma/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Adulto , Linfócitos T CD4-Positivos/metabolismo , Biologia Computacional/métodos , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Glioma/imunologia , Glioma/mortalidade , Humanos , Masculino , Células Mieloides/metabolismo , Gradação de Tumores/métodos , Neutrófilos/metabolismo , Prognóstico , Intervalo Livre de Progressão , Fatores de Risco , Software
7.
Nat Commun ; 12(1): 3379, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099719

RESUMO

GATA3 is as a lineage-specific transcription factor that drives the differentiation of CD4+ T helper 2 (Th2) cells, but is also involved in a variety of processes such as immune regulation, proliferation and maintenance in other T cell and non-T cell lineages. Here we show a mechanism utilised by CD4+ T cells to increase mitochondrial mass in response to DNA damage through the actions of GATA3 and AMPK. Activated AMPK increases expression of PPARG coactivator 1 alpha (PPARGC1A or PGC1α protein) at the level of transcription and GATA3 at the level of translation, while DNA damage enhances expression of nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2). PGC1α, GATA3 and NRF2 complex together with the ATR to promote mitochondrial biogenesis. These findings extend the pleotropic interactions of GATA3 and highlight the potential for GATA3-targeted cell manipulation for intervention in CD4+ T cell viability and function after DNA damage.


Assuntos
Linfócitos T CD4-Positivos/citologia , Dano ao DNA , Fator de Transcrição GATA3/metabolismo , Mitocôndrias/metabolismo , Biogênese de Organelas , Proteínas Quinases Ativadas por AMP/metabolismo , Adulto , Linfócitos T CD4-Positivos/metabolismo , Sobrevivência Celular/genética , Células Cultivadas , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Humanos , Pessoa de Meia-Idade , Fator 2 Relacionado a NF-E2/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Cultura Primária de Células
8.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065512

RESUMO

Multisubunit cullin-RING ubiquitin ligase 4 (CRL4)-DCAF12 recognizes the C-terminal degron containing acidic amino acid residues. However, its physiological roles and substrates are largely unknown. Purification of CRL4-DCAF12 complexes revealed a wide range of potential substrates, including MOV10, an "ancient" RNA-induced silencing complex (RISC) complex RNA helicase. We show that DCAF12 controls the MOV10 protein level via its C-terminal motif in a proteasome- and CRL-dependent manner. Next, we generated Dcaf12 knockout mice and demonstrated that the DCAF12-mediated degradation of MOV10 is conserved in mice and humans. Detailed analysis of Dcaf12-deficient mice revealed that their testes produce fewer mature sperms, phenotype accompanied by elevated MOV10 and imbalance in meiotic markers SCP3 and γ-H2AX. Additionally, the percentages of splenic CD4+ T and natural killer T (NKT) cell populations were significantly altered. In vitro, activated Dcaf12-deficient T cells displayed inappropriately stabilized MOV10 and increased levels of activated caspases. In summary, we identified MOV10 as a novel substrate of CRL4-DCAF12 and demonstrated the biological relevance of the DCAF12-MOV10 pathway in spermatogenesis and T cell activation.


Assuntos
Antígenos de Neoplasias/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Células T Matadoras Naturais/metabolismo , RNA Helicases/metabolismo , Espermatogênese/fisiologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Ativação Linfocitária/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo
9.
Front Immunol ; 12: 616309, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968018

RESUMO

Memory T cells are crucial for both local and systemic protection against pathogens over a long period of time. Three major subsets of memory T cells; effector memory T (TEM) cells, central memory T (TCM) cells, and tissue-resident memory T (TRM) cells have been identified. The most recently identified subset, TRM cells, is characterized by the expression of the C-type lectin CD69 and/or the integrin CD103. TRM cells persist locally at sites of mucosal tissue, such as the lung, where they provide frontline defense against various pathogens. Importantly, however, TRM cells are also involved in shaping the pathology of inflammatory diseases. A number of pioneering studies revealed important roles of CD8+ TRM cells, particularly those in the local control of viral infection. However, the protective function and pathogenic role of CD4+ TRM cells that reside within the mucosal tissue remain largely unknown. In this review, we discuss the ambivalent feature of CD4+ TRM cells in the protective and pathological immune responses. We also review the transcriptional and epigenetic characteristics of CD4+ TRM cells in the lung that have been elucidated by recent technical approaches. A better understanding of the function of CD4+ TRM cells is crucial for the development of both effective vaccination against pathogens and new therapeutic strategies for intractable inflammatory diseases, such as inflammatory bowel diseases and chronic allergic diseases.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Imunidade nas Mucosas , Memória Imunológica , Membrana Mucosa/imunologia , Membrana Mucosa/metabolismo , Plasticidade Celular/imunologia , Suscetibilidade a Doenças , Epigênese Genética , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Especificidade de Órgãos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
10.
Cell Prolif ; 54(7): e13056, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34021647

RESUMO

OBJECTIVES: In contrast to extensive studies on bone metastasis in advanced prostate cancer (PCa), liver metastasis has been under-researched so far. In order to decipher molecular and cellular mechanisms underpinning liver metastasis of advanced PCa, we develop a rapid and immune sufficient mouse model for liver metastasis of PCa via orthotopic injection of organoids from PbCre+ ; rb1f/f ;p53f/f mice. MATERIALS AND METHODS: PbCre+ ;rb1f/f ;p53f/f and PbCre+ ;ptenf/f ;p53f/f mice were used to generate PCa organoid cultures in vitro. Immune sufficient liver metastasis models were established via orthotopic transplantation of organoids into the prostate of C57BL/6 mice. Immunofluorescent and immunohistochemical staining were performed to characterize the lineage profile in primary tumour and organoid-derived tumour (ODT). The growth of niche-labelling reporter infected ODT can be visualized by bioluminescent imaging system. Immune cells that communicated with tumour cells in the liver metastatic niche were determined by flow cytometry. RESULTS: A PCa liver metastasis model with full penetrance is established in immune-intact mouse. This model reconstitutes the histological and lineage features of original tumours and reveals dynamic tumour-immune cell communication in liver metastatic foci. Our results suggest that a lack of CD8+ T cell and an enrichment of CD163+ M2-like macrophage as well as PD1+ CD4+ T cell contribute to an immuno-suppressive microenvironment of PCa liver metastasis. CONCLUSIONS: Our model can be served as a reliable tool for analysis of the molecular pathogenesis and tumour-immune cell crosstalk in liver metastasis of PCa, and might be used as a valuable in vivo model for therapy development.


Assuntos
Neoplasias Hepáticas/patologia , Neoplasias da Próstata/patologia , Animais , 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 , Comunicação Celular , Modelos Animais de Doenças , Neoplasias Hepáticas/secundário , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/genética , Neoplasias da Próstata/metabolismo , Microambiente Tumoral , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética
11.
Immunity ; 54(7): 1578-1593.e5, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34051147

RESUMO

Immune profiling of COVID-19 patients has identified numerous alterations in both innate and adaptive immunity. However, whether those changes are specific to SARS-CoV-2 or driven by a general inflammatory response shared across severely ill pneumonia patients remains unknown. Here, we compared the immune profile of severe COVID-19 with non-SARS-CoV-2 pneumonia ICU patients using longitudinal, high-dimensional single-cell spectral cytometry and algorithm-guided analysis. COVID-19 and non-SARS-CoV-2 pneumonia both showed increased emergency myelopoiesis and displayed features of adaptive immune paralysis. However, pathological immune signatures suggestive of T cell exhaustion were exclusive to COVID-19. The integration of single-cell profiling with a predicted binding capacity of SARS-CoV-2 peptides to the patients' HLA profile further linked the COVID-19 immunopathology to impaired virus recognition. Toward clinical translation, circulating NKT cell frequency was identified as a predictive biomarker for patient outcome. Our comparative immune map serves to delineate treatment strategies to interfere with the immunopathologic cascade exclusive to severe COVID-19.


Assuntos
COVID-19/imunologia , SARS-CoV-2/patogenicidade , Adulto , Enzima de Conversão de Angiotensina 2/metabolismo , Apresentação do Antígeno , Biomarcadores/sangue , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , COVID-19/patologia , Feminino , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Imunidade Inata , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/imunologia , Pneumonia/imunologia , Pneumonia/patologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
12.
Biomed Res Int ; 2021: 5535578, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981768

RESUMO

Muscle-invasive bladder cancer (MIBC) is characterized by a highly complex immune environment, which is not well understood. Interleukin-6 (IL-6) is generated and secreted by multifarious types of cells, including tumor cells. This study was aimed at demonstrating that the levels of IL-6 and the number of myeloid-derived suppressor cells (MDSCs), with a positive correlation between them, increased in MIBC tissues, promoting MIBC cell proliferation, especially in patients with recurrence. In coculture analysis, MDSCs, with the stimulation of IL-6, could significantly lower the proliferation ability of CD4+ or CD8+ T lymphocytes. Further, this study demonstrated that IL-6 could upregulate the mitogen-activated protein kinase (MAPK) signaling pathway in MDSCs. The MAPK signaling inhibitor, aloesin, partially reversed the effects of IL-6 on MDSCs. These data suggested that IL-6 promoted MIBC progression by not only accelerating proliferation but also improving the immune suppression ability of MDSCs through activating the MAPK signaling pathway.


Assuntos
Interleucina-6/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Células Supressoras Mieloides , Neoplasias da Bexiga Urinária , Idoso , Idoso de 80 Anos ou mais , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células/fisiologia , Humanos , Camundongos , Pessoa de Meia-Idade , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Transdução de Sinais/fisiologia , Bexiga Urinária/química , Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/mortalidade
13.
Front Immunol ; 12: 620386, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936035

RESUMO

Cytomegalovirus (CMV) is one of the most commonly recognized opportunistic pathogens and remains the most influential known parameter in shaping an individual's immune system. As such, T cells induced by CMV infection could have a long-term impact on subsequent immune responses. Accumulating evidence indicates that memory T cells developed during past bacterial and viral infection can cross-react with unrelated pathogens, including transplant antigens, and can alter responses to de novo infections, vaccines, cancers, or rejection. Therefore, careful examination of T cell responses elicited by CMV is warranted to understand their potentially beneficial or harmful roles in future major immune events. Our detailed exploration of the distribution, phenotype, TCR repertoire and transcriptome of CD4+ T cells within CMV seropositive healthy individuals using high-dimensional flow cytometry and single cell multi-omics sequencing reveals that CMV seropositivity has highly significant age-independent effects, leading to a reduction in CD4+ naïve T cells and an expansion of CD4+ effector memory T cells and CD45RA+ effector memory T cells. These induced CD4+ effector memory T cells undergo a specific differentiation trajectory resulting in a subpopulation of CD57+CD27-CD28-CD244+ CD4+ T cells with cytotoxic function and TCR oligoclonality for optimal controlled coexistence with cytomegalovirus. Through gene set enrichment analysis, we found that this subpopulation is similar to virus-specific CD8+ T cells and T cells that mediate acute rejection in patients using tacrolimus and belatacept, a selective costimulation blocker. Together, these data suggest that memory CD4+ T cells induced by cytomegalovirus are formed via a distinct differentiation program to acquire cytotoxic function and can be potentially detrimental to transplant patients adopting costimulation blockade immunosuppressive regimen.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Citomegalovirus/imunologia , Interações Hospedeiro-Patógeno/imunologia , Abatacepte/farmacologia , Abatacepte/uso terapêutico , Adulto , Antígenos CD/metabolismo , Biomarcadores , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/metabolismo , Citotoxicidade Imunológica , Feminino , Perfilação da Expressão Gênica , Humanos , Memória Imunológica , Imunofenotipagem , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
14.
Nat Commun ; 12(1): 2475, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931637

RESUMO

An innovative approach to eliminate HIV-1-infected cells emerging out of latency, the major hurdle to HIV-1 cure, is to pharmacologically reactivate viral expression and concomitantly trigger intracellular pro-apoptotic pathways in order to selectively induce cell death (ICD) of infected cells, without reliance on the extracellular immune system. In this work, we demonstrate the effect of DDX3 inhibitors on selectively inducing cell death in latent HIV-1-infected cell lines, primary CD4+ T cells and in CD4+ T cells from cART-suppressed people living with HIV-1 (PLWHIV). We used single-cell FISH-Flow technology to characterise the contribution of viral RNA to inducing cell death. The pharmacological targeting of DDX3 induced HIV-1 RNA expression, resulting in phosphorylation of IRF3 and upregulation of IFNß. DDX3 inhibition also resulted in the downregulation of BIRC5, critical to cell survival during HIV-1 infection, and selectively induced apoptosis in viral RNA-expressing CD4+ T cells but not bystander cells. DDX3 inhibitor treatment of CD4+ T cells from PLWHIV resulted in an approximately 50% reduction of the inducible latent HIV-1 reservoir by quantitation of HIV-1 RNA, by FISH-Flow, RT-qPCR and TILDA. This study provides proof of concept for pharmacological reversal of latency coupled to induction of apoptosis towards the elimination of the inducible reservoir.


Assuntos
Apoptose/efeitos dos fármacos , Azepinas/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , RNA Helicases DEAD-box/metabolismo , Infecções por HIV/imunologia , HIV-1/metabolismo , Imidazóis/farmacologia , Latência Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Antirretrovirais/farmacologia , Apoptose/genética , Azepinas/química , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , RNA Helicases DEAD-box/antagonistas & inibidores , RNA Helicases DEAD-box/química , Inibidores Enzimáticos/farmacologia , Infecções por HIV/genética , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Imidazóis/química , Hibridização in Situ Fluorescente , Fator Regulador 3 de Interferon/metabolismo , Interferon beta/metabolismo , Células Jurkat , Simulação de Acoplamento Molecular , RNA Viral/metabolismo , Análise de Célula Única , Survivina/metabolismo , Ativação Viral/efeitos dos fármacos , Replicação Viral/genética
15.
Eur J Endocrinol ; 185(1): 145-154, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-33960958

RESUMO

Objective: Autoimmune Addison's disease (AD) results from a combination of the genetic predisposition, unclear environmental triggers and ensuing immune dysfunction. MicroRNA molecules (miRNAs) are involved in post-transcriptional regulation of numerous target genes, hence may affect the immune function and promote autoimmunity. A deregulated miRNAs profile was reported in several autoimmune conditions. Our study was aimed at a global analysis of miRNA expression in CD4+ T cells from patients with AD. Methods: CD4+ T cells were separated from peripheral blood, total RNA enriched in miRNAs extracted, and miRNA expression determined by small RNA sequencing. Global miRNA was investigated in 11 AD subjects and 9 age-matched healthy controls, with subsequent validation of the differentially expressed miRNAs by RT-qPCR in 29 patients and 28 controls. Results: The analysis revealed upregulation of 9 miRNAs and downregulation of miR-509-3p in CD4+ T cells from patients with AD (cut-off fold change (FC) >2, Benjamini-Hochberg P < 0.05). RT-qPCR validation confirmed overexpression of miR-7977 (P < 0.0001, FC = 2.7), miR-374a-5p and miR-1260b (P < 0.05, FC = 1.3 and 1.2, respectively). miR-7977 was upregulated in patients with coexisting autoimmune conditions vs those with isolated AD (P = 0.005, mean FC = 2.2). Moreover, miR-7977 abundance appeared correlated with the number of autoimmune comorbidities (P <0.0001, r = 0.736) and serum autoantibodies against thyroid peroxidase (P < 0.001, r = 0.588). Conclusions: Our study demonstrates upregulated expression of miR-7977 in CD4+ T cells from patients with AD, especially with its polyendocrine form. Further analyses are warranted to replicate our results, establish the marker utility of miR-7977, and elucidate its functional role in autoimmunity.


Assuntos
Doença de Addison/genética , Doença de Addison/imunologia , Autoimunidade/genética , Linfócitos T CD4-Positivos/metabolismo , MicroRNAs/genética , Regulação para Cima , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/sangue , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de RNA
16.
Nat Commun ; 12(1): 3010, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34021148

RESUMO

Resident memory T cells (TRM) positioned within the respiratory tract are probably required to limit SARS-CoV-2 spread and COVID-19. Importantly, TRM are mostly non-recirculating, which reduces the window of opportunity to examine these cells in the blood as they move to the lung parenchyma. Here, we identify circulating virus-specific T cell responses during acute infection with functional, migratory and apoptotic patterns modulated by viral proteins and associated with clinical outcome. Disease severity is associated predominantly with IFNγ and IL-4 responses, increased responses against S peptides and apoptosis, whereas non-hospitalized patients have increased IL-12p70 levels, degranulation in response to N peptides and SARS-CoV-2-specific CCR7+ T cells secreting IL-10. In convalescent patients, lung-TRM are frequently detected even 10 months after initial infection, in which contemporaneous blood does not reflect tissue-resident profiles. Our study highlights a balanced anti-inflammatory antiviral response associated with a better outcome and persisting TRM cells as important for future protection against SARS-CoV-2 infection.


Assuntos
COVID-19/imunologia , Memória Imunológica/imunologia , Pulmão/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Apoptose/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , COVID-19/virologia , Movimento Celular/imunologia , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-4/imunologia , Interleucina-4/metabolismo , Pulmão/virologia , SARS-CoV-2/fisiologia , Linfócitos T/metabolismo
17.
Med J Malaysia ; 76(3): 446-448, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34031352

RESUMO

Coronavirus Disease 2019 (COVID-19) is an acute respiratory infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection that started in Wuhan, China in December 2019 and has spread rapidly worldwide. It's critical to take extra precautions if a person has chronic illnesses (comorbidities), such as human immunodeficiency (HIV) infection. Concerns about people living with HIV (PLHIV) having a higher risk of serious COVID-19 disease may be based on the assumption that PLHIV are more likely to be immunocompromised. On the other hand, limited information is available in such people about the characteristics of co-infection between SARS-CoV-2 and Human Immunodeficiency Virus (HIV) who are at greater risk than the general population. Our findings, is of a 32 year old patient who came to Emergency Unit of Wangaya Hospital, Medical Faculty, Udayana University in Denpasar, Bali with complaint of fever, dry cough, and shortness of breath since prior 3 days and had also the past history prolonged fever, weight loss more than 10% 4 weeks. Diagnosis of COVID-19 was confirmed by nasopharyngeal swab sample was used for RT-PCR assay and PITC to confirm HIV infection. He had prolonged hospitalized and discharge after 18 days.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , COVID-19/diagnóstico , Coinfecção/diagnóstico , Infecções por HIV/diagnóstico , Adulto , Biomarcadores/sangue , COVID-19/sangue , COVID-19/imunologia , Coinfecção/sangue , Coinfecção/imunologia , Infecções por HIV/sangue , Infecções por HIV/imunologia , Humanos , Masculino
18.
Mol Immunol ; 134: 202-209, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33813201

RESUMO

Accruing research shows the implications of long non-coding RNAs (lncRNAs) in the progression of various autoimmune diseases including systemic lupus erythematosus (SLE). The present study aimed to identify the expression pattern of LINC00176 in SLE and to explore its effects on CD4+T cell adhesion in this context. The biological functions of LINC00176, WIF1 and WNT5a on CD4+T cells in SLE were evaluated via gain- and loss-of-function experiments, following delivery of pcDNA3-LINC00176, siRNA-LINC00176, pcDNA3-WIF1 and WNT-sFRP5 (an inhibitor for the WNT5a signaling pathway). High LINC00176 expression was evident in the CD4+T cells of SLE patients. Additionally, WIF1 was identified as a potential target gene of LINC00176, and was negatively regulated by LINC00176. The overexpression of LINC00176 could promote proliferation and adhesion of CD4+T cells in SLE. Such alternations were reversed following up-regulation of WIF1 or inhibition of the WNT5a signaling pathway. Taken together, the key findings of our study highlight the ability of LINC00176 to potentially promote the proliferation and adhesion of CD4+T cells in SLE by down-regulating WIF1 and activating the WNT5a signaling pathway, providing new insight and a theoretical basis for translation in SLE therapy.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Linfócitos T CD4-Positivos/imunologia , Regulação da Expressão Gênica/fisiologia , Lúpus Eritematoso Sistêmico/imunologia , RNA Longo não Codificante/imunologia , Proteína Wnt-5a/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Adulto , Linfócitos T CD4-Positivos/metabolismo , Adesão Celular/imunologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Masculino , RNA Longo não Codificante/metabolismo , Transdução de Sinais/fisiologia , Proteína Wnt-5a/metabolismo , Adulto Jovem
19.
Front Immunol ; 12: 617592, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33912153

RESUMO

Pregravid obesity has been shown to disrupt the development of the offspring's immune system and increase susceptibility to infection. While the mechanisms underlying the impact of maternal obesity on fetal myeloid cells are emerging, the consequences for T cells remain poorly defined. In this study, we collected umbilical cord blood samples from infants born to lean mothers and mothers with obesity and profiled CD4 T cells using flow cytometry and single cell RNA sequencing at resting and following ex vivo polyclonal stimulation. We report that maternal obesity is associated with higher frequencies of memory CD4 T cells suggestive of in vivo activation. Moreover, single cell RNA sequencing revealed expansion of an activated subset of memory T cells with maternal obesity. However, ex vivo stimulation of purified CD4 T cells resulted in poor cytokine responses, suggesting functional defects. These phenotypic and functional aberrations correlated with methylation and chromatin accessibility changes in loci associated with lymphocyte activation and T cell receptor signaling, suggesting a possible link between maternal obesogenic environment and fetal immune reprogramming. These observations offer a potential explanation for the increased susceptibility to microbial infection in babies born to mothers with obesity.


Assuntos
Biomarcadores , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Epigênese Genética , Sangue Fetal/citologia , Imunofenotipagem , Montagem e Desmontagem da Cromatina , Citocinas/metabolismo , Metilação de DNA , Feminino , Perfilação da Expressão Gênica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Obesidade Materna/sangue , Obesidade Materna/genética , Obesidade Materna/imunologia , Obesidade Materna/metabolismo , Gravidez , Análise de Célula Única/métodos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Transcriptoma
20.
J Infect Dis ; 224(1): 70-80, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-33822097

RESUMO

Herein we measured CD4+ T-cell responses against common cold coronaviruses (CCC) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in high-risk health care workers (HCW) and community controls. We observed higher levels of CCC-reactive T cells in SARS-CoV-2-seronegative HCW compared to community donors, consistent with potential higher occupational exposure of HCW to CCC. We further show that SARS-CoV-2 T-cell reactivity of seronegative HCW was higher than community controls and correlation between CCC and SARS-CoV-2 responses is consistent with cross-reactivity and not associated with recent in vivo activation. Surprisingly, CCC T-cell reactivity was decreased in SARS-CoV-2-infected HCW, suggesting that exposure to SARS-CoV-2 might interfere with CCC responses, either directly or indirectly. This result was unexpected, but consistently detected in independent cohorts derived from Miami and San Diego. CD4+ T-cell responses against common cold coronaviruses (CCC) are elevated in SARS-CoV-2 seronegative high-risk health care workers (HCW) compared to COVID-19 convalescent HCW, suggesting that exposure to SARS-CoV-2 might interfere with CCC responses and/or cross-reactivity associated with a protective effect.


Assuntos
COVID-19/epidemiologia , COVID-19/imunologia , Pessoal de Saúde , SARS-CoV-2/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Anticorpos Antivirais , Biomarcadores , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , COVID-19/diagnóstico , COVID-19/virologia , Ensaio de Imunoadsorção Enzimática , Epitopos de Linfócito T/química , Epitopos de Linfócito T/imunologia , Feminino , Humanos , Imunofenotipagem , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Peptídeos/química , Peptídeos/imunologia , Vigilância em Saúde Pública , Estudos Soroepidemiológicos , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/imunologia , Subpopulações de Linfócitos T/metabolismo
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