RESUMEN
The main barrier to a cure for HIV is the persistence of long-lived and proliferating latently infected CD4+ T-cells despite antiretroviral therapy (ART). Latency is well characterized in multiple CD4+ T-cell subsets, however, the contribution of regulatory T-cells (Tregs) expressing FoxP3 as well as immune checkpoints (ICs) PD-1 and CTLA-4 as targets for productive and latent HIV infection in people living with HIV on suppressive ART is less well defined. We used multiplex detection of HIV DNA and RNA with immunohistochemistry (mIHC) on formalin-fixed paraffin embedded (FFPE) cells to simultaneously detect HIV RNA and DNA and cellular markers. HIV DNA and RNA were detected by in situ hybridization (ISH) (RNA/DNAscope) and IHC was used to detect cellular markers (CD4, PD-1, FoxP3, and CTLA-4) by incorporating the tyramide system amplification (TSA) system. We evaluated latently infected cell lines, a primary cell model of HIV latency and excisional lymph node (LN) biopsies collected from people living with HIV (PLWH) on and off ART. We clearly detected infected cells that coexpressed HIV RNA and DNA (active replication) and DNA only (latently infected cells) in combination with IHC markers in the in vitro infection model as well as LN tissue from PLWH both on and off ART. Combining ISH targeting HIV RNA and DNA with IHC provides a platform to detect and quantify HIV persistence within cells identified by multiple markers in tissue samples from PLWH on ART or to study HIV latency.
Asunto(s)
ADN Viral/análisis , Infecciones por VIH/diagnóstico , VIH/genética , Inhibidores de Puntos de Control Inmunológico/análisis , Inmunohistoquímica , Hibridación in Situ , Infección Latente/diagnóstico , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/virología , ARN Viral/análisis , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Células Jurkat , Infección Latente/inmunología , Infección Latente/virología , Valor Predictivo de las Pruebas , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/virologíaRESUMEN
Treg/Th17 cell imbalance and inflammatory response may occur in neonatal asthma. IL-35 and BCG have inhibitory effects on inflammatory responses in diseases. However, studies on neonatal asthma after combination of the two have not been reported so far. A respiratory syncytial virus (RSV)-induced neonatal asthma model was first developed in newborn mice. Pathological sections of lung tissue of asthmatic mice were observed by HE staining. Masson staining was used to observe the lung tissue and to compare the deposition of collagen fibers under bronchial epithelium in model mice. The expression of cytokines in serum was detected by ELISA. Giemsa staining analyzed each cell in bronchoalveolar lavage fluid (BALF). Flow cytometry was used to detect the differentiation and development of Treg and Th17 subgroups in BALF. The expression levels of inflammation-related factors were detected by RT-qPCR. Western blot was used to detect the expression of JNK pathway-related proteins. Recombinant IL-35-BCG improved the pathological response of asthmatic mice; inhibited the expression of IgE in serum, neutrophils, macrophages, and eosinophils in BALF; and increased the expression of lymphocytes. In addition, recombinant IL-35-BCG significantly inhibited Th17 differentiation, promoted Treg cell differentiation, and inhibited the expression of inflammatory factors in lung tissue homogenates, thereby reducing allergic airway inflammation. This process might be achieved by inhibiting the JNK signaling pathway. Recombinant IL-35-BCG can regulate Treg/Th17 cell imbalance and inflammatory response in asthmatic newborn mice induced by RSV through JNK signaling pathway, suggesting a new path to neonatal asthma treatment.
Asunto(s)
Antiasmáticos/farmacología , Antiinflamatorios/farmacología , Asma/tratamiento farmacológico , Vacuna BCG/farmacología , Interleucinas/farmacología , Pulmón/efectos de los fármacos , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Linfocitos T Reguladores/efectos de los fármacos , Células Th17/efectos de los fármacos , Animales , Animales Recién Nacidos , Asma/inmunología , Asma/metabolismo , Asma/virología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Mediadores de Inflamación/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Pulmón/inmunología , Pulmón/inervación , Pulmón/virología , Ratones Endogámicos BALB C , Proteínas Recombinantes/farmacología , Infecciones por Virus Sincitial Respiratorio/inmunología , Infecciones por Virus Sincitial Respiratorio/metabolismo , Infecciones por Virus Sincitial Respiratorio/virología , Virus Sincitiales Respiratorios/patogenicidad , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/virología , Células Th17/inmunología , Células Th17/metabolismo , Células Th17/virologíaRESUMEN
The hallmark of severe COVID-19 is an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We hypothesized that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, correlating with poor outcomes. These Tregs showed a distinct transcriptional signature, with overexpression of several suppressive effectors, but also proinflammatory molecules like interleukin (IL)-32, and a striking similarity to tumor-infiltrating Tregs that suppress antitumor responses. Most marked during acute severe disease, these traits persisted somewhat in convalescent patients. A screen for candidate agents revealed that IL-6 and IL-18 may individually contribute different facets of these COVID-19-linked perturbations. These results suggest that Tregs may play nefarious roles in COVID-19, by suppressing antiviral T cell responses during the severe phase of the disease, and by a direct proinflammatory role.
Asunto(s)
COVID-19/etiología , Linfocitos T Reguladores/fisiología , Adulto , Anciano , Linfocitos T CD4-Positivos/virología , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Inflamación/metabolismo , Inflamación/virología , Interleucina-18/genética , Interleucina-18/metabolismo , Subunidad alfa del Receptor de Interleucina-2/genética , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Linfocitos Infiltrantes de Tumor/fisiología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/virología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
We recently reported that the risk of sexually acquired HIV-1 infection is increased significantly by variants in the gene encoding CD101, a protein thought to modify inflammatory responses. Using blood samples from individuals with and without these variants, we demonstrate that CD101 variants modify the prevalence of circulating inflammatory cell types and show that CD101 variants are associated with increased proinflammatory cytokine production by circulating T cells. One category of CD101 variants is associated with a reduced capacity of regulatory T cells to suppress T cell cytokine production, resulting in a reduction in the baseline level of immune quiescence. These data are supported by transcriptomics data revealing alterations in the intrinsic regulation of antiviral pathways and HIV resistance genes in individuals with CD101 variants. Our data support the hypothesis that CD101 contributes to homeostatic regulation of bystander inflammation, with CD101 variants altering heterosexual HIV-1 acquisition by facilitating increased prevalence and altered function of T cell subsets.
Asunto(s)
Antígenos CD/genética , Linaje de la Célula/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Mutación , Linfocitos T Reguladores/inmunología , Adulto , Antígenos CD/inmunología , Linfocitos B/inmunología , Linfocitos B/virología , Células Dendríticas/inmunología , Células Dendríticas/virología , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Infecciones por VIH/transmisión , Infecciones por VIH/virología , Humanos , Inmunidad Innata , Inmunofenotipificación , Masculino , Monocitos/inmunología , Monocitos/virología , Fenotipo , Receptores CCR5/genética , Receptores CCR5/inmunología , Receptores CXCR4/genética , Receptores CXCR4/inmunología , Linfocitos T Reguladores/virologíaRESUMEN
Viral hepatitis is a devastating disease with the risk for cirrhosis and carcinogenicity. Regulatory T cells (Tregs) play important roles in the disease course of viral hepatitis via maintaining the balance between overt-immune responses and viral replications. We hypothesized that genetic polymorphisms of Treg-related genes, such as interleukin-2, transforming growth factor-ß 1 (TGF-ß1), forkhead box P3 (FOXP3), and adenylyl cyclase type 9 modulate the hosts' immune regulation under circumstances of viral hepatitis. We examined the effect of five single nucleotide polymorphisms (SNPs) of Treg-related genes on the levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), alanine aminotransferase, and non-invasive hepatic fibrosis marker (Fibrosis-4 index) in a total of 138 participants with viral hepatitis. The rs1800469 (a TGF-ß1 SNP) GG genotype is associated with higher serum CRP levels, and the rs3761547 (a FOXP3 SNP) C allele in the females is associated with higher ESR levels. Besides, female participants carrying the rs3761547 C allele had a significantly higher Fibrosis-4 (FIB-4) index than the females carrying the TT genotype, while the rs3761547 C allele had the opposite effect in males. With linear-regression moderation analysis, we found that sex moderated the impact of the FOXP3 SNP on the levels of FIB-4, whereas the FOXP3 SNP caused the opposite effect between males and females on the severity of hepatic fibrosis. These results provide evidence for the participation of TGF-ß1 and FOXP3 in the inflammatory responses associated with viral hepatitis, where FOXP3 function may be moderated by sex.
Asunto(s)
Adenilil Ciclasas/genética , Factores de Transcripción Forkhead/genética , Hepatitis B Crónica/genética , Hepatitis C Crónica/genética , Polimorfismo de Nucleótido Simple , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta1/genética , Adenilil Ciclasas/inmunología , Anciano , Proteína C-Reactiva/genética , Proteína C-Reactiva/inmunología , Femenino , Factores de Transcripción Forkhead/inmunología , Expresión Génica , Genotipo , Hepacivirus/inmunología , Hepacivirus/patogenicidad , Antígenos de Superficie de la Hepatitis B/genética , Antígenos de Superficie de la Hepatitis B/inmunología , Virus de la Hepatitis B/inmunología , Virus de la Hepatitis B/patogenicidad , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/patología , Hepatitis B Crónica/virología , Hepatitis C Crónica/inmunología , Hepatitis C Crónica/patología , Hepatitis C Crónica/virología , Humanos , Inmunoglobulina G/genética , Inmunoglobulina G/inmunología , Inflamación , Masculino , Persona de Mediana Edad , Linfocitos T Reguladores/virología , Factor de Crecimiento Transformador beta1/inmunologíaRESUMEN
Adult T-cell leukemia-lymphoma (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1) infection. Among HTLV-1 encoded genes, HTLV-1 bZIP factor (HBZ) and tax are critical for the leukemogenesis of ATL. Adult T-cell leukemia-lymphoma needs a long latent period before onset, indicating that both viral genes and alterations (genetic and epigenetic) of the host genome play important roles for leukemogenesis. Viral genes influence genetic and epigenetic changes of the host genome, indicating that the virus is of primary importance in leukemogenesis. HBZ is expressed in all ATL cases, whereas Tax expression is heterogeneous among ATL cases. Different patterns of viral gene expression in tumors are also observed for Epstein-Barr virus. We propose three subtypes of ATL cases based on Tax expression: high, intermittent, and lost expression. HBZ is detected in all ATL cases. Approximately 25% of all ATL cases lost Tax expression at infection of HTLV-1, indicating that HBZ is the only viral gene responsible for leukemogenesis in addition to genetic and epigenetic changes of the host genes in these ATL cases. The host immune responses to Tax are also implicated in the heterogeneity of ATL. Thus, ATL is a heterogeneous disease in terms of its viral gene expression, which is important for pathogenesis of this intractable lymphomatous neoplasm.
Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Productos del Gen tax/genética , Herpesvirus Humano 4/genética , Virus Linfotrópico T Tipo 1 Humano/genética , Leucemia-Linfoma de Células T del Adulto/virología , Proteínas de los Retroviridae/genética , Animales , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Linfocitos B/virología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/inmunología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Proliferación Celular , Transformación Celular Viral , Epigénesis Genética , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación Leucémica de la Expresión Génica , Regulación Viral de la Expresión Génica , Productos del Gen tax/inmunología , Productos del Gen tax/metabolismo , Humanos , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/inmunología , Leucemia-Linfoma de Células T del Adulto/metabolismo , Ratones , Ratones Transgénicos , ARN Viral/genética , Proteínas de los Retroviridae/inmunología , Proteínas de los Retroviridae/metabolismo , Linfocitos T Reguladores/virología , Replicación Viral/genéticaRESUMEN
The adaptive immune system has the enormous challenge to protect the host through the generation and differentiation of pathogen-specific short-lived effector T cells while in parallel developing long-lived memory cells to control future encounters with the same pathogen. A complex regulatory network is needed to preserve a population of naïve cells over lifetime that exhibit sufficient diversity of antigen receptors to respond to new antigens, while also sustaining immune memory. In parallel, cells need to maintain their proliferative potential and the plasticity to differentiate into different functional lineages. Initial signs of waning immune competence emerge after 50 years of age, with increasing clinical relevance in the 7th-10th decade of life. Morbidity and mortality from infections increase, as drastically exemplified by the current COVID-19 pandemic. Many vaccines, such as for the influenza virus, are poorly effective to generate protective immunity in older individuals. Age-associated changes occur at the level of the T-cell population as well as the functionality of its cellular constituents. The system highly relies on the self-renewal of naïve and memory T cells, which is robust but eventually fails. Genetic and epigenetic modifications contribute to functional differences in responsiveness and differentiation potential. To some extent, these changes arise from defective maintenance; to some, they represent successful, but not universally beneficial adaptations to the aging host. Interventions that can compensate for the age-related defects and improve immune responses in older adults are increasingly within reach.
Asunto(s)
Envejecimiento/inmunología , COVID-19/inmunología , Células T de Memoria/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Inmunidad Adaptativa , Anciano , Envejecimiento/genética , COVID-19/genética , COVID-19/patología , COVID-19/virología , Diferenciación Celular , Proliferación Celular , Fosfatasa 6 de Especificidad Dual/genética , Fosfatasa 6 de Especificidad Dual/inmunología , Regulación de la Expresión Génica , Humanos , Células T de Memoria/virología , MicroARNs/genética , MicroARNs/inmunología , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/inmunología , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva/inmunología , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Linfocitos T Citotóxicos/virología , Linfocitos T Colaboradores-Inductores/virología , Linfocitos T Reguladores/virologíaRESUMEN
HIV infection is a major risk factor predisposing for Mycobacterium tuberculosis infection and progression to active tuberculosis (TB). As host immune response defines the course of infection, we aimed to identify immuno-endocrine changes over six-months of anti-TB chemotherapy in HIV+ people. Plasma levels of cortisol, DHEA and DHEA-S, percentages of CD4+ regulatory T cell subsets and number of IFN-γ-secreting cells were determined. Several cytokines, chemokines and C-reactive protein levels were measured. Results were correlated with clinical parameters as predictors of infection resolution and compared to similar data from HIV+ individuals, HIV-infected persons with latent TB infection and healthy donors. Throughout the course of anti-TB/HIV treatment, DHEA and DHEA-S plasma levels raised while cortisol diminished, which correlated to predictive factors of infection resolution. Furthermore, the balance between cortisol and DHEA, together with clinical assessment, may be considered as an indicator of clinical outcome after anti-TB treatment in HIV+ individuals. Clinical improvement was associated with reduced frequency of unconventional Tregs, increment in IFN-γ-secreting cells, diminution of systemic inflammation and changes of circulating cytokines and chemokines. This study suggests that the combined anti-HIV/TB therapies result in partial restoration of both, immune function and adrenal hormone plasma levels.
Asunto(s)
Corticoesteroides/sangre , Antituberculosos/uso terapéutico , Infecciones por VIH/sangre , VIH-1/patogenicidad , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Adulto , Biomarcadores/sangre , Coinfección , Citocinas/sangre , Deshidroepiandrosterona/sangre , Sulfato de Deshidroepiandrosterona/sangre , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , Interacciones Huésped-Patógeno , Humanos , Hidrocortisona/sangre , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/patogenicidad , Estudios Prospectivos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/microbiología , Linfocitos T Reguladores/virología , Factores de Tiempo , Resultado del Tratamiento , Tuberculosis/sangre , Tuberculosis/inmunología , Tuberculosis/microbiologíaAsunto(s)
Leucocitos Mononucleares/inmunología , Infecciones por Papillomavirus/genética , Infecciones del Sistema Respiratorio/genética , Linfocitos T Reguladores/inmunología , Gemelos Dicigóticos/genética , Alphapapillomavirus/genética , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Preescolar , Cidofovir/administración & dosificación , Cidofovir/uso terapéutico , Expresión Génica/genética , Humanos , Laringoscopía/métodos , Leucocitos Mononucleares/metabolismo , Masculino , Recurrencia Local de Neoplasia/cirugía , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/cirugía , Infecciones por Papillomavirus/virología , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/patología , Infecciones del Sistema Respiratorio/cirugía , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/virologíaRESUMEN
As the number of infections and mortalities from the SARS-CoV-2 pandemic continues to rise, the development of an effective therapy against COVID-19 becomes ever more urgent. A few reports showing a positive correlation between BCG vaccination and reduced COVID-19 mortality have ushered in some hope. BCG has been suggested to confer a broad level of nonspecific protection against several pathogens, mainly via eliciting "trained immunity" in innate immune cells. Secondly, BCG has also been proven to provide benefits in autoimmune diseases by inducing tolerogenicity. Being an acute inflammatory disease, COVID-19 requires a therapy that induces early priming of anti-viral immune responses and regulates aberrant hyperactivity of innate-immune cells. Here, we hypothesize that BCG can offer reliable spatiotemporal protection from COVID-19 by triggering trained immunity and tolerogenesis, through multiple cellular pathways. We propose further research on BCG-mediated immunoprotection, especially in vulnerable individuals, as a strategy to halt the progress of the SARS-CoV-2 pandemic. Also see the video abstract here https://youtu.be/P2D2RXfq6Vg.
Asunto(s)
Vacuna BCG/uso terapéutico , COVID-19/prevención & control , Síndrome de Liberación de Citoquinas/prevención & control , Tolerancia Inmunológica/efectos de los fármacos , Inmunidad Innata/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos B/virología , COVID-19/inmunología , COVID-19/patología , COVID-19/virología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/patología , Síndrome de Liberación de Citoquinas/virología , Citocinas/genética , Citocinas/inmunología , Regulación de la Expresión Génica , Humanos , Memoria Inmunológica/efectos de los fármacos , Moléculas de Patrón Molecular Asociado a Patógenos/inmunología , Moléculas de Patrón Molecular Asociado a Patógenos/metabolismo , ARN Viral/genética , ARN Viral/inmunología , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/virología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/virología , Vacunación/métodosRESUMEN
In novel coronavirus disease 2019 (COVID-19), the increased frequency and overactivation of T helper (Th) 17 cells and subsequent production of large amounts of proinflammatory cytokines result in hyperinflammation and disease progression. The current study aimed to investigate the therapeutic effects of nanocurcumin on the frequency and responses of Th17 cells in mild and severe COVID-19 patients. In this study, 40 severe COVID-19 intensive care unit-admitted patients and 40 patients in mild condition were included. The frequency of Th17 cells, the messenger RNA expression of Th17 cell-related factors (RAR-related orphan receptor γt, interleukin [IL]-17, IL-21, IL-23, and granulocyte-macrophage colony-stimulating factor), and the serum levels of cytokines were measured in both nanocurcumin and placebo-treated groups before and after treatment. A significant decrease in the number of Th17 cells, downregulation of Th17 cell-related factors, and decreased levels of Th17 cell-related cytokines were found in mild and severe COVID-19 patients treated by nanocurcumin compared to the placebo group. Moreover, the abovementioned parameters were significantly decreased in the nanocurcumin-treated group after treatment versus before treatment. Curcumin could reduce the frequency of Th17 cells and their related inflammatory factors in both mild and severe COVID-19 patients. Hence, it could be considered as a potential modulatory compound in improving the patient's inflammatory condition.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Curcumina/uso terapéutico , Inmunomodulación/efectos de los fármacos , Nanopartículas/uso terapéutico , Células Th17/efectos de los fármacos , Adulto , Citocinas/metabolismo , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Nanopartículas/administración & dosificación , SARS-CoV-2/efectos de los fármacos , Índice de Severidad de la Enfermedad , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/virología , Células Th17/metabolismoRESUMEN
Regulatory T cells (Tregs) prevent excessive immune responses and limit immune pathology upon infections. To fulfill this role in different immune environments elicited by different types of pathogens, Tregs undergo functional specialization into distinct subsets. During acute type 1 immune responses, type 1 Tregs are induced and recruited to the site of ongoing Th1 responses to efficiently control Th1 responses. However, whether a similar specialization process also takes place following chronic infections is still unknown. In this study, we investigated Treg specialization in persistent viral infections using lymphocytic choriomeningitis virus (LCMV) and murine cytomegalovirus (MCMV) infection as models for chronic and latent infections, respectively. We identify CD85k as a Th1-specific co-inhibitory receptor with sustained expression in persistent viral infections and show that recombinant CD85k inhibits LCMV-specific effector T cells. Furthermore, expression of the CD85k ligand ALCAM is induced on LCMV-specific and exhausted T cells during chronic LCMV infection. Finally, we demonstrate that type 1 Tregs arising during chronic LCMV infection suppress Th1 effector cells in an ALCAM-dependent manner. These results extend the current knowledge of Treg specialization from acute to persistent viral infections and reveal an important functional role of CD85k in Treg-mediated suppression of type 1 immunity.
Asunto(s)
Virus de la Coriomeningitis Linfocítica/inmunología , Glicoproteínas de Membrana/inmunología , Muromegalovirus/inmunología , Receptores Inmunológicos/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígenos CD/inmunología , Antígenos CD/metabolismo , Moléculas de Adhesión Celular Neuronal/inmunología , Moléculas de Adhesión Celular Neuronal/metabolismo , Línea Celular , Células Cultivadas , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/metabolismo , Infecciones por Herpesviridae/virología , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/metabolismo , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/fisiología , Glicoproteínas de Membrana/metabolismo , Ratones Endogámicos C57BL , Muromegalovirus/fisiología , Receptores Inmunológicos/metabolismo , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/virología , Células TH1/inmunología , Células TH1/metabolismoRESUMEN
Recurrent herpes labialis (RHL) is a common skin disease that is often caused by herpes simplex virus type I (HSV-1), but its immunology and pathogenesis remain unclear. The balance of Th17/Treg cells is crucial for maintaining immune homeostasis. This study aimed to investigate whether the balance of Th17/Treg cells and related cytokines may be a determinant occurrence in patients with RHL. This is a clinical experimental research based on clinical observation and analysis. We collected RHL patients from the outpatient clinic of the Department of Dermatology of Zhejiang Chinese Medical University (Hangzhou, China) in 2017, conducted questionnaire survey and signed informed consent. Peripheral blood was collected from 30 patients with RHL and 30 healthy volunteers. Flow cytometry was used to detect the percentages of Treg cells and Th17 cells. Protein microarrays coated with 20 cytokines related to T-cell subsets were performed. Enzyme-linked immunosorbent assay (ELISA) assay was conducted to further verify the expression levels of the cytokines that were screened by protein microarrays. Percentages of Th17/Treg cells in peripheral blood of RHL patients were significantly increased compared to those in healthy volunteers. The fold changes of GM-CSF, IL-4, TGF-ß, IL-12, IL-10, IL-17F, and TNF-α were significantly increased compared with healthy volunteers. In addition, the expression of IL-4, IL-10, and TGF-ß in the serum of RHL patients increased significantly. Our results indicated an imbalance of Th17/Treg cells in RHL, and this imbalance is probably an important factor in the occurrence, development, and recovery of RHL.
Asunto(s)
Herpes Labial/inmunología , Herpesvirus Humano 1/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Adulto , Estudios de Casos y Controles , Diferenciación Celular , Citocinas/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Herpes Labial/sangre , Herpes Labial/diagnóstico , Herpes Labial/virología , Herpesvirus Humano 1/patogenicidad , Interacciones Huésped-Patógeno , Humanos , Inmunofenotipificación , Mediadores de Inflamación/sangre , Masculino , Persona de Mediana Edad , Análisis por Matrices de Proteínas , Recurrencia , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/virología , Células Th17/metabolismo , Células Th17/virología , Adulto JovenAsunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Fiebre/inmunología , Mialgia/inmunología , Trastornos del Olfato/inmunología , Neumonía Viral/inmunología , Adulto , COVID-19 , Estudios de Casos y Controles , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/virología , Síndrome de Liberación de Citoquinas/complicaciones , Síndrome de Liberación de Citoquinas/diagnóstico , Síndrome de Liberación de Citoquinas/virología , Progresión de la Enfermedad , Femenino , Fiebre/complicaciones , Fiebre/diagnóstico , Fiebre/virología , Humanos , Inmunidad Innata , Mialgia/complicaciones , Mialgia/diagnóstico , Mialgia/virología , Trastornos del Olfato/complicaciones , Trastornos del Olfato/diagnóstico , Trastornos del Olfato/virología , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/diagnóstico , Neumonía Viral/virología , Embarazo , SARS-CoV-2 , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/virología , Balance Th1 - Th2 , Células Th2/inmunología , Células Th2/virologíaRESUMEN
BACKGROUND: T-regulatory cells (Tregs) play an important role in maintaining homeostasis by attenuating the cytokine response to T-cell receptor (TCR) stimulation and by suppressing the functioning of neighboring immune cells. In Human Immunodeficiency Virus (HIV) infection, Tregs can be either beneficial, by suppressing generalized T-cell activation, or detrimental, by suppressing protective anti-HIV cell-mediated immunity. An imbalance of Tregs and effector T-cells can blunt immune responses to malignant cells or facilitate inflammation-mediated pathologies. OBJECTIVE: The purpose of our study was to explore the possible correlation between Tregs' concentration and HIV infection's parameters as well as the development of hematological and solid malignancies. METHODS: In a longitudinal prospective study, ex vivo phenotyping of fresh peripheral blood mononuclear cells from patients with primary HIV infection was performed at baseline. All patients were then followed up every 3 months and the development of solid or hematological malignancies was noted. RESULTS: A total of 155 patients were included in the study and the median follow-up period was 64 months. Treg counts were significantly higher among males, patients with high viral load (>350 copies/ml) and patients with virological failure to antiretroviral treatment (ART). Linear regression analysis showed a significant negative correlation between Treg levels and CD4 (+) T-cell counts. Patients with neoplasia had lower levels of Tregs while increasing levels showed a negative correlation with the development of neoplasia. CONCLUSION: In our population of HIV-infected patients, high levels of Tregs were associated with disease progression, and low baseline levels were associated with a higher probability of developing neoplasia.
Asunto(s)
Infecciones por VIH/inmunología , VIH/inmunología , Inmunidad Celular , Neoplasias/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Progresión de la Enfermedad , Femenino , VIH/genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/mortalidad , Infecciones por VIH/virología , Humanos , Inmunofenotipificación , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Neoplasias/virología , Estudios Prospectivos , Análisis de Supervivencia , Linfocitos T Citotóxicos/patología , Linfocitos T Citotóxicos/virología , Linfocitos T Reguladores/patología , Linfocitos T Reguladores/virología , Carga Viral/efectos de los fármacosRESUMEN
EBV-associated gastric carcinoma (EBVaGC) is accompanied by massive lymphocyte infiltration, but therapy resistance and tumor progression still occur in patients with EBVaGC. Cancer stem cells (CSCs) are reported to possess immunomodulatory ability that allows them to resist immune-mediated rejection for many tumor types. However, whether and how CSCs in EBVaGC exhibit immunosuppression has not yet been elucidated. We isolated CSC-like sphere-forming cells (SFCs) from EBVaGC cell line SNU-719 using the cancer sphere method. We validated their CSC-associated properties in the expression of the epithelial-mesenchymal transition (EMT)-related genes, the ability to form colonies, and resistance to chemotherapy drug-induced apoptosis and explored their immunomodulatory ability using the coculture system with PBMC (peripheral blood mononuclear cell). These CSC-like SFCs were CD44+CD24-/low and were more tumorigenic than the parental SNU-719 cells in the xenograft mouse model. Remarkably, in the tumor-PBMC co-culturing experiments, these EBVaGC SFCs demonstrated profound immunosuppression by inhibiting the proliferation of PBMCs and T cell activation as well as inducing the generation of regulatory T cells (Tregs). Furthermore, the induction of Tregs was partially dependent on prostaglandin E2 (PGE2) produced from SFCs. Moreover, the presence of high CD44+CD24-/low cells in tumor tissues predicted a decreased disease-free survival in patients with EBVaGC. Our study collectively confirmed the existence and immune resistance of CSCs in EBVaGC and offers new insights into the development of novel anti-EBVaGC strategies by targeting CSCs.
Asunto(s)
Antígeno CD24/inmunología , Carcinoma/inmunología , Dinoprostona/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Regulación Neoplásica de la Expresión Génica , Receptores de Hialuranos/inmunología , Neoplasias Gástricas/inmunología , Adulto , Anciano , Animales , Antígeno CD24/genética , Carcinoma/complicaciones , Carcinoma/genética , Carcinoma/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Dinoprostona/biosíntesis , Transición Epitelial-Mesenquimal/genética , Transición Epitelial-Mesenquimal/inmunología , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/patología , Femenino , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 4/patogenicidad , Humanos , Receptores de Hialuranos/genética , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Transducción de Señal , Esferoides Celulares/inmunología , Esferoides Celulares/patología , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Linfocitos T Reguladores/virología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Inflammation triggered by influenza A virus (IAV) infection is important for viral clearance, induction of adaptive responses, and return to lung homeostasis. However, an exaggerated immune response, characterized by the overproduction of chemokines, can lead to intense lung injury, contributing to mortality. Chemokine scavenger receptors, such as ACKR2, control the levels of CC chemokines influencing the immune responses. Among the chemokine targets of ACKR2, CCL5 is important to recruit and activate lymphocytes. We investigated the role of ACKR2 during IAV infection in mice. Pulmonary ACKR2 expression was increased acutely after IAV infection preceding the virus-induced lung dysfunction. ACKR2-knockout (ACKR2-/-) mice were protected from IAV, presenting decreased viral burden and lung dysfunction. Mechanistically, the absence of ACKR2 resulted in augmented airway CCL5 levels, secreted by mononuclear and plasma cells in the lung parenchyma. The higher chemokine gradient led to an augmented recruitment of T and B lymphocytes, formation of inducible bronchus-associated lymphoid tissue and production of IgA in the airways of ACKR2-/- mice post-IAV. CCL5 neutralization in ACKR2-/- mice prevented lymphocyte recruitment and increased bronchoalveolar lavage fluid protein levels and pulmonary dysfunction. Finally, CCR5-/- mice presented increased disease severity during IAV infection, displaying increased neutrophils, pulmonary injury and dysfunction, and accentuated lethality. Collectively, our data showed that ACKR2 dampens CCL5 levels and the consequent recruitment of CCR5+ T helper 1 (Th1), T regulatory cells (Tregs), and B lymphocytes during IAV infection, decreasing pathogen control and promoting lung dysfunction in wild type mice. Therefore, ACKR2 is detrimental and CCR5 is protective during IAV infection coordinating innate and adaptive immune responses in mice.
Asunto(s)
Linfocitos B/metabolismo , Quimiocina CCL5/metabolismo , Pulmón/metabolismo , Infecciones por Orthomyxoviridae/metabolismo , Receptores CCR5/metabolismo , Receptores de Quimiocina/metabolismo , Linfocitos T Reguladores/metabolismo , Animales , Linfocitos B/virología , Líquido del Lavado Bronquioalveolar/virología , Virus de la Influenza A/patogenicidad , Pulmón/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Orthomyxoviridae/virología , Linfocitos T Reguladores/virologíaRESUMEN
BACKGROUNDS: Regulatory T cells (Tregs) affect the pathogenesis of chronic hepatitis C (CHC) infection. AIMS: This study evaluated the function of Tregs in CHC patients receiving the standard direct-acting antiviral agents (DAA) treatment. METHODS: CHC patients (n = 20) who received DAA treatment, clinical data, and function of Tregs were checked at baseline, Week 4, end of treatment (EOT), and 12 weeks after EOT (SVR 12). Treg-mediated inhibition was measured. The cytokine expression and fold change of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-10, and transforming growth factor (TGF)-ß with/without Treg inhibition were also detected. RESULTS: The cohort included 14 females with a mean age of 59.8 ± 11.5 years. Nineteen had HCV genotype 1. The HCV RNA level was 6.17 ± 0.70 log IU/mL. All patients reached the sustained virologic response. The frequency of CD4+Foxp3+T cells decreased from baseline to EOT and returned at SVR 12. The inhibitory function of Tregs decreased during treatment and then restored (baseline vs. EOT, P = 0.0393; EOT vs. SVR 12, P = 0.0052). The cytokine expression and fold change of IFN-γ and TNF-α were highest at EOT and then decreased at SVR 12. The fold change of IL-10 was lowest at EOT and then increased at SVR 12. The fold change of TGF-ß was significantly increased at Week 4 and SVR 12 compared to baseline. CONCLUSIONS: The frequency and inhibitory function of Tregs declined gradually from baseline to EOT and then increased from EOT to SVR 12 in CHC patients receiving DAA therapy. The expression of IFN-γ, TNF-α, IL-10, and TGF-ß parallelled Treg function.
Asunto(s)
Antivirales/uso terapéutico , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Linfocitos T Reguladores/virología , Anciano , Citocinas/sangre , Femenino , Genotipo , Hepatitis C Crónica/sangre , Hepatitis C Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Respuesta Virológica SostenidaRESUMEN
Dengue virus (DENV) can cause diseases ranging from dengue fever (DF) to more severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Whether antiviral T cells contribute to the protection against or pathogenesis of severe disease is not well defined. Here, we identified antigen-specific IL-10+IFN-γ+ double-positive (DP) CD4 T cells during acute DENV infection. While the transcriptomic signatures of DP cells partially overlapped with those of cytotoxic and type 1 regulatory CD4 T cells, the majority of them were non-cytotoxic/Tr1 and included IL21, IL22, CD109, and CCR1. Although we observed a higher frequency of DP cells in DHF, the transcriptomic profile of DP cells was similar in DF and DHF, suggesting that DHF is not associated with the altered phenotypic or functional attributes of DP cells. Overall, this study revealed a DENV-specific DP cell subset in patients with acute dengue disease and argues against altered DP cells as a determinant of DHF.
Asunto(s)
Virus del Dengue/inmunología , Regulación de la Expresión Génica/inmunología , Interferón gamma/inmunología , Interleucina-10/inmunología , Dengue Grave/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunología , Adolescente , Adulto , Antígenos CD/genética , Antígenos CD/inmunología , Estudios de Casos y Controles , Virus del Dengue/patogenicidad , Femenino , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/inmunología , Humanos , Interferón gamma/genética , Interleucina-10/genética , Interleucinas/genética , Interleucinas/inmunología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Receptores CCR1/genética , Receptores CCR1/inmunología , Dengue Grave/genética , Dengue Grave/patología , Dengue Grave/virología , Índice de Severidad de la Enfermedad , Transducción de Señal , Linfocitos T Citotóxicos/virología , Linfocitos T Reguladores/virología , Transcriptoma/inmunología , Interleucina-22RESUMEN
Background: Treg cells represent important viral reservoirs during chronic HIV infection. CD39 is closely involved in Treg-mediated immunosuppressive effects. However, CD39 expression on nTregs and mTregs and a relationship with HIV DNA levels during HIV infection is still unclear. In this study, we analyzed the distribution of HIV DNA in Treg subsets and the association between HIV DNA and CD39 expression on Treg subsets. Methods: Sixty-two HIV-infected patients with different HIV stages and 14 uninfected individuals were enrolled. nTregs (CD4+CD25+CD127lowCD45RO-) and mTregs (CD4+CD25+CD127lowCD45RO+) were isolated by magnetic selection and flow cytometric sorting. HIV DNA was quantified by real-time polymerase chain reaction (PCR). CD39 expression on nTregs and mTregs was analyzed by flow cytometry. Results: Higher levels of HIV DNA were detected in mTregs than those in nTregs during chronic HIV infection. The frequency of CD39+ nTregs and HIV DNA levels in nTregs were increased in patients with advanced HIV infection. Furthermore, HIV DNA levels in nTregs correlated positively with CD39+ nTreg frequency. CD39+ nTreg frequency was also increased in immune non-responders. Conclusions: mTregs and nTregs are both important reservoirs of virus during chronic HIV infection and HIV DNA levels increase in nTregs in patients with advanced HIV infection. We observed increased frequency of CD39+ nTregs and HIV DNA levels in nTregs in patients with advanced HIV infection. HIV DNA levels in nTregs correlated positively with CD39+ nTreg frequency.