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1.
Front Immunol ; 12: 626308, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33854501

RESUMEN

We have previously shown that conformational change in the ß2-integrin is a very early activation marker that can be detected with fluorescent multimers of its ligand intercellular adhesion molecule (ICAM)-1 for rapid assessment of antigen-specific CD8+ T cells. In this study, we describe a modified protocol of this assay for sensitive detection of functional antigen-specific CD4+ T cells using a monoclonal antibody (clone m24 Ab) specific for the open, high-affinity conformation of the ß2-integrin. The kinetics of ß2-integrin activation was different on CD4+ and CD8+ T cells (several hours vs. few minutes, respectively); however, m24 Ab readily stained both cell types 4-6 h after antigen stimulation. With this protocol, we were able to monitor ex vivo effector and memory CD4+ and CD8+ T cells specific for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and hepatitis B virus (HBV) in whole blood or cryopreserved peripheral blood mononuclear cells (PBMCs) of infected or vaccinated individuals. By costaining ß2-integrin with m24 and CD154 Abs, we assessed extremely low frequencies of polyfunctional CD4+ T cell responses. The novel assay used in this study allows very sensitive and simultaneous screening of both CD4+ and CD8+ T cell reactivities, with versatile applicability in clinical and vaccination studies.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Interacciones Huésped-Patógeno/inmunología , Integrinas/metabolismo , Adulto , Anciano , Secuencia de Aminoácidos , Sitios de Unión , /inmunología , /virología , Proteínas Portadoras/química , Citocinas/metabolismo , Citomegalovirus/inmunología , Epítopos de Linfocito T/química , Epítopos de Linfocito T/inmunología , Femenino , Antígenos HLA/química , Antígenos HLA/inmunología , Interacciones Huésped-Patógeno/genética , Humanos , Inmunohistoquímica , Inmunofenotipificación , Integrinas/genética , Molécula 1 de Adhesión Intercelular/química , Molécula 1 de Adhesión Intercelular/metabolismo , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Unión Proteica , Multimerización de Proteína , Especificidad del Receptor de Antígeno de Linfocitos T , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo
2.
Front Immunol ; 12: 636118, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33854506

RESUMEN

Following respiratory viral infections or local immunizations, lung resident-memory T cells (TRM) of the CD8 lineage provide protection against the same pathogen or related pathogens with cross-reactive T cell epitopes. Yet, it is now clear that, if homeostatic controls are lost following viral pneumonia, CD8 TRM cells can mediate pulmonary pathology. We recently showed that the aging process can result in loss of homeostatic controls on CD8 TRM cells in the respiratory tract. This may be germane to treatment modalities in both influenza and coronavirus disease 2019 (COVID-19) patients, particularly, the portion that present with symptoms linked to long-lasting lung dysfunction. Here, we review the developmental cues and functionalities of CD8 TRM cells in viral pneumonia models with a particular focus on their capacity to mediate heterogeneous responses of immunity and pathology depending on immune status.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , /virología , Memoria Inmunológica , Pulmón/inmunología , Pulmón/virología , /inmunología , Factores de Edad , Animales , Biomarcadores , Linfocitos T CD8-positivos/metabolismo , /patología , Resistencia a la Enfermedad/inmunología , Homeostasis , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunofenotipificación , Pulmón/metabolismo , Pulmón/patología , Recuento de Linfocitos , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología
3.
Front Immunol ; 12: 645741, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33854510

RESUMEN

Particulate matter (PM) induces neutrophilic inflammation and deteriorates the prognosis of diseases such as cardiovascular diseases, cancers, and infections, including COVID-19. Here, we addressed the role of γδ T cells and intestinal microbiome in PM-induced acute neutrophilia. γδ T cells are a heterogeneous population composed of Tγδ1, Tγδ2, Tγδ17, and naïve γδ T cells (TγδN) and commensal bacteria promote local expansion of Tγδ17 cells, particularly in the lung and gut without affecting their Vγ repertoire. Tγδ17 cells are more tissue resident than Tγδ1 cells, while TγδN cells are circulating cells. IL-1R expression in Tγδ17 cells is highest in the lung and they outnumber all the other type 17 cells such as Th17, ILC3, NKT17, and MAIT17 cells. Upon PM exposure, IL-1ß-secreting neutrophils and IL-17-producing Tγδ17 cells attract each other around the airways. Accordingly, PM-induced neutrophilia was significantly relieved in γδ T- or IL-17-deficient and germ-free mice. Collectively, these findings show that the commensal microbiome promotes PM-induced neutrophilia in the lung via Tγδ17 cells.


Asunto(s)
Leucocitosis/etiología , Pulmón/inmunología , Microbiota , Neutrófilos/patología , Material Particulado/efectos adversos , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Animales , Asma/etiología , Asma/metabolismo , Asma/patología , Biomarcadores , Citocinas/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Técnica del Anticuerpo Fluorescente , Inmunidad Innata , Inmunofenotipificación , Leucocitosis/metabolismo , Leucocitosis/patología , Pulmón/metabolismo , Pulmón/patología , Ratones , Neutrófilos/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo
4.
Front Immunol ; 12: 666983, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33854516

RESUMEN

The emergence of viruses with pandemic potential such as the SARS-CoV-2 coronavirus causing COVID-19 poses a global health challenge. There is remarkable progress in vaccine technology in response to this threat, but their design often overlooks the innate arm of immunity. Gamma Delta (γδ) T cells are a subset of T cells with unique features that gives them a key role in the innate immune response to a variety of homeostatic alterations, from cancer to microbial infections. In the context of viral infection, a growing body of evidence shows that γδ T cells are particularly equipped for early virus detection, which triggers their subsequent activation, expansion and the fast deployment of antiviral functions such as direct cytotoxic pathways, secretion of cytokines, recruitment and activation of other immune cells and mobilization of a trained immunity memory program. As such, γδ T cells represent an attractive target to stimulate for a rapid and effective resolution of viral infections. Here, we review the known aspects of γδ T cells that make them crucial component of the immune response to viruses, and the ways that their antiviral potential can be harnessed to prevent or treat viral infection.


Asunto(s)
/inmunología , Interacciones Huésped-Patógeno , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Inmunidad Adaptativa , Animales , Terapia Combinada , Citotoxicidad Inmunológica , Manejo de la Enfermedad , Susceptibilidad a Enfermedades/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad Innata , Receptores Inmunológicos/metabolismo
5.
Med Sci Monit ; 27: e930853, 2021 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-33844678

RESUMEN

BACKGROUND COVID-19 has become a worldwide epidemic disease and is a public health crisis. We aim to provide evidence for clinical diagnosis and assessment of severity by analyzing patients' clinical data and early laboratory results and exploring the correlation between laboratory results and clinical classification. MATERIAL AND METHODS We enrolled 283 cases of suspected and diagnosed COVID-19 from 16 hospitals in Jiangsu Province from January to April 2020. The routine laboratory blood examinations, T lymphocyte subsets, and biochemical and coagulation function among different populations were contrasted by t test and chi-square (χ²) test. RESULTS Cough, fever, and dyspnea could be helpful to diagnose COVID-19 infection (P<0.05). Patients who were older or had comorbidities tended to become severe and critical cases. Among all the patients, the most obvious abnormal laboratory results were higher neutrophil count, CRP, total bilirubin, BUN, CRE, APTT, PT, and D-dimer, and lower blood platelet and lymphocyte count. CD3⁺ T cell, CD4⁺ T cell, and CD8⁺ T cell counts gradually decreased with exacerbation of the disease (P<0.05). CONCLUSIONS Cough and fever were the most common symptom. Patients with comorbidities were in more serious condition. The detection of inflammatory indexes, coagulation function, lymphocyte subsets, and renal function can help diagnose and assess the severity of COVID-19.


Asunto(s)
/diagnóstico , Tos/epidemiología , Fiebre/epidemiología , Índice de Severidad de la Enfermedad , Adulto , Anciano , Anciano de 80 o más Años , Coagulación Sanguínea/inmunología , /complicaciones , China/epidemiología , Comorbilidad , Tos/sangre , Tos/inmunología , Tos/virología , Femenino , Fiebre/sangre , Fiebre/inmunología , Fiebre/virología , Humanos , Inflamación/sangre , Inflamación/diagnóstico , Inflamación/inmunología , Inflamación/virología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Subgrupos de Linfocitos T/inmunología , Adulto Joven
6.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-33800867

RESUMEN

During tissue injury events, the innate immune system responds immediately to alarms sent from the injured cells, and the adaptive immune system subsequently joins in the inflammatory reaction. The control mechanism of each immune reaction relies on the orchestration of different types of T cells and the activators, antigen-presenting cells, co-stimulatory molecules, and cytokines. Mitochondria are an intracellular signaling organelle and energy plant, which supply the energy requirement of the immune system and maintain the system activation with the production of reactive oxygen species (ROS). Extracellular mitochondria can elicit regenerative effects or serve as an activator of the immune cells to eliminate the damaged cells. Recent clarification of the cytosolic escape of mitochondrial DNA triggering innate immunity underscores the pivotal role of mitochondria in inflammation-related diseases. Human mesenchymal stem cells could transfer mitochondria through nanotubular structures to defective mitochondrial DNA cells. In recent years, mitochondrial therapy has shown promise in treating heart ischemic events, Parkinson's disease, and fulminating hepatitis. Taken together, these results emphasize the emerging role of mitochondria in immune-cell-mediated tissue regeneration and ageing.


Asunto(s)
Envejecimiento/inmunología , Células Presentadoras de Antígenos/inmunología , Subgrupos de Linfocitos B/inmunología , Mitocondrias/fisiología , Regeneración/inmunología , Subgrupos de Linfocitos T/inmunología , Inmunidad Adaptativa , Animales , Citocinas/fisiología , ADN/metabolismo , ADN Mitocondrial/metabolismo , Reposicionamiento de Medicamentos , Péptido 1 Similar al Glucagón/agonistas , Homeostasis , Humanos , Inmunidad Innata , Inflamación , Péptidos y Proteínas de Señalización Intercelular/fisiología , Lupus Eritematoso Sistémico/tratamiento farmacológico , Metformina/farmacología , Metformina/uso terapéutico , Mitocondrias/efectos de los fármacos , Proteínas Mitocondriales/fisiología , Especies Reactivas de Oxígeno/metabolismo , Inmunología del Trasplante , Heridas y Traumatismos/inmunología , Heridas y Traumatismos/fisiopatología
7.
Front Immunol ; 12: 614599, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33692788

RESUMEN

Widespread coronavirus disease (COVID)-19 is causing pneumonia, respiratory and multiorgan failure in susceptible individuals. Dysregulated immune response marks severe COVID-19, but the immunological mechanisms driving COVID-19 pathogenesis are still largely unknown, which is hampering the development of efficient treatments. Here we analyzed ~140 parameters of cellular and humoral immune response in peripheral blood of 41 COVID-19 patients and 16 age/gender-matched healthy donors by flow-cytometry, quantitative PCR, western blot and ELISA, followed by integrated correlation analyses with ~30 common clinical and laboratory parameters. We found that lymphocytopenia in severe COVID-19 patients (n=20) strongly affects T, NK and NKT cells, but not B cells and antibody production. Unlike increased activation of ICOS-1+ CD4+ T cells in mild COVID-19 patients (n=21), T cells in severe patients showed impaired activation, low IFN-γ production and high functional exhaustion, which correlated with significantly down-regulated HLA-DR expression in monocytes, dendritic cells and B cells. The latter phenomenon was followed by lower interferon responsive factor (IRF)-8 and autophagy-related genes expressions, and the expansion of myeloid derived suppressor cells (MDSC). Intriguingly, PD-L1-, ILT-3-, and IDO-1-expressing monocytic MDSC were the dominant producers of IL-6 and IL-10, which correlated with the increased inflammation and accumulation of regulatory B and T cell subsets in severe COVID-19 patients. Overall, down-regulated IRF-8 and autophagy-related genes expression, and the expansion of MDSC subsets could play critical roles in dysregulating T cell response in COVID-19, which could have large implications in diagnostics and design of novel therapeutics for this disease.


Asunto(s)
Proteínas Relacionadas con la Autofagia/biosíntesis , Células Supresoras de Origen Mieloide/inmunología , Subgrupos de Linfocitos T/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Autofagia/inmunología , Proteínas Relacionadas con la Autofagia/inmunología , Proteínas Relacionadas con la Autofagia/metabolismo , /patología , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Inmunidad , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Células Supresoras de Origen Mieloide/patología , Subgrupos de Linfocitos T/patología , Linfocitos T/inmunología
8.
Proc Natl Acad Sci U S A ; 118(12)2021 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-33688035

RESUMEN

Modified vaccinia virus Ankara (MVA) is a replication-restricted smallpox vaccine, and numerous clinical studies of recombinant MVAs (rMVAs) as vectors for prevention of other infectious diseases, including COVID-19, are in progress. Here, we characterize rMVAs expressing the S protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Modifications of full-length S individually or in combination included two proline substitutions, mutations of the furin recognition site, and deletion of the endoplasmic retrieval signal. Another rMVA in which the receptor binding domain (RBD) is flanked by the signal peptide and transmembrane domains of S was also constructed. Each modified S protein was displayed on the surface of rMVA-infected cells and was recognized by anti-RBD antibody and soluble hACE2 receptor. Intramuscular injection of mice with the rMVAs induced antibodies, which neutralized a pseudovirus in vitro and, upon passive transfer, protected hACE2 transgenic mice from lethal infection with SARS-CoV-2, as well as S-specific CD3+CD8+IFNγ+ T cells. Antibody boosting occurred following a second rMVA or adjuvanted purified RBD protein. Immunity conferred by a single vaccination of hACE2 mice prevented morbidity and weight loss upon intranasal infection with SARS-CoV-2 3 wk or 7 wk later. One or two rMVA vaccinations also prevented detection of infectious SARS-CoV-2 and subgenomic viral mRNAs in the lungs and greatly reduced induction of cytokine and chemokine mRNAs. A low amount of virus was found in the nasal turbinates of only one of eight rMVA-vaccinated mice on day 2 and none later. Detection of low levels of subgenomic mRNAs in turbinates indicated that replication was aborted in immunized animals.


Asunto(s)
/inmunología , Vectores Genéticos/genética , Vacunas de ADN/inmunología , Virus Vaccinia/genética , /genética , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Especificidad de Anticuerpos/inmunología , /genética , Modelos Animales de Enfermedad , Expresión Génica , Humanos , Inmunización , Inmunización Pasiva , Inmunoglobulina G/inmunología , Ratones , Ratones Transgénicos , Glicoproteína de la Espiga del Coronavirus/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Vacunas de ADN/administración & dosificación , Vacunas de ADN/genética
9.
Sci Signal ; 14(673)2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33688079

RESUMEN

IL-1ß is a key mediator of the cytokine storm linked to high morbidity and mortality from COVID-19, and IL-1ß blockade with anakinra and canakinumab during COVID-19 infection has entered clinical trials. Using mass cytometry of human peripheral blood mononuclear cells, we identified effector memory CD4+ T cells and CD4-CD8low/-CD161+ T cells, specifically those positive for the chemokine receptor CCR6, as the circulating immune subtypes with the greatest response to IL-1ß. This response manifested as increased phosphorylation and, thus, activation of the proinflammatory transcription factor NF-κB and was also seen in other subsets, including CD11c+ myeloid dendritic cells, classical monocytes, two subsets of natural killer cells (CD16-CD56brightCD161- and CD16-CD56dimCD161+), and lineage- (Lin-) cells expressing CD161 and CD25. IL-1ß also induced a rapid but less robust increase in the phosphorylation of the kinase p38 as compared to that of NF-κB in most of these immune cell subsets. Prolonged IL-1ß stimulation increased the phosphorylation of the transcription factor STAT3 and to a lesser extent that of STAT1 and STAT5 across various immune cell types. IL-1ß-induced production of IL-6 likely led to the activation of STAT1 and STAT3 at later time points. Interindividual heterogeneity and inhibition of STAT activation by anakinra raise the possibility that assays measuring NF-κB phosphorylation in response to IL-1ß in CCR6+ T cell subtypes could identify those patients at higher risk of cytokine storm and most likely to benefit from IL-1ß-neutralizing therapies.


Asunto(s)
/inmunología , Interleucina-1beta/sangre , Subgrupos de Linfocitos T/inmunología , /sangre , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Citometría de Flujo , Humanos , Interleucina-1beta/farmacología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Monocitos/clasificación , Monocitos/inmunología , Monocitos/metabolismo , FN-kappa B/sangre , Pandemias , Fosforilación , Receptores CCR6/sangre , Factores de Transcripción STAT/sangre , Factores de Transcripción STAT/inmunología , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/sangre
10.
J Immunother Cancer ; 9(3)2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33707314

RESUMEN

While vaccines directed against the SARS-CoV-2 spike protein will have varying degrees of effectiveness in preventing SARS-CoV-2 infections, the severity of infection will be determined by multiple host factors including the ability of immune cells to lyse virus-infected cells. This review will discuss the complexity of both adaptive and innate immunomes and how a flow-based assay can detect up to 158 distinct cell subsets in the periphery. This assay has been employed to show the effect of age on differences in specific immune cell subsets, and the differences in the immunome between healthy donors and age-matched cancer patients. Also reviewed are the numerous soluble factors, in addition to cytokines, that may vary in the pathogenesis of SARS-CoV-2 infections and may also be employed to help define the effectiveness of a given vaccine or other antiviral agents. Various steroids have been employed in the management of autoimmune adverse events in cancer patients receiving immunotherapeutics and may be employed in the management of SARS-CoV-2 infections. The influence of steroids on multiple immune cells subsets will also be discussed.


Asunto(s)
Inmunidad Adaptativa/inmunología , Linfocitos B/inmunología , Células Dendríticas/inmunología , Inmunidad Innata/inmunología , Células Asesinas Naturales/inmunología , Neoplasias/inmunología , Linfocitos T/inmunología , Factores de Edad , Antígeno B7-H1/inmunología , Ligando de CD40/inmunología , /uso terapéutico , Citocinas/inmunología , Susceptibilidad a Enfermedades , Glucocorticoides/uso terapéutico , Granzimas/inmunología , Humanos , Inmunosenescencia/inmunología , Células Supresoras de Origen Mieloide/inmunología , Neoplasias/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/inmunología , Proteoma , Índice de Severidad de la Enfermedad , Subgrupos de Linfocitos T/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología
11.
Front Immunol ; 12: 581469, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33664741

RESUMEN

Background: Epidemiological factors, clinical characteristics, and risk factors for the mortality of COVID-19 patients have been studied, but the role of complementary systems, possible inflammatory and immune response mechanisms, and detailed clinical courses are uncertain and require further study. Methods: In this single center, retrospective case-control study, we included all COVID-19 inpatients transferred or admitted to Wuhan Tongji Hospital from January 3 to March 30 2020 who had definite clinical outcomes (cured or deceased) with complete laboratory and radiological results. Clinical data were extracted from the electronic medical records, and compared between the cured and deceased patients. ROC curves were used to evaluate the prognostic value of the clinical parameters, and multivariable logistic regression analysis was performed to explore the risk factors for mortality. The correlation between the variables was evaluated by Spearman correlation analysis. Results: 208 patients were included in this study, 182 patients were cured and discharged, 26 patients died from COVID-2019. Most patients had comorbidities, with hypertension as the most common chronic disease (80; 38%). The most common symptoms at onset were fever (149; 72%), cough (137; 66%), and dyspnea (113; 54%). Elevated leucocytes, neutrophils, inflammatory biomarkers (CRP, ferritin, IL6, IL8, procalcitonin), PT, D-dimer, myocardial enzymes, BUN, decreased lymphocyte and subsets (T cells, CD4 T cells, CD8 T cells, NK cells, T cells + B cells + NK cells), and immunological factors (C3, C4) indicated poor outcome. PT, C3, and T cells were confirmed as independent prognostic factors for mortality by logistic regression models. IL6 and CPR were positively correlated with neutrophils, but negatively with lymphocytes and lymphocyte subsets except B cells. IL8 and ferritin were negatively related to T cells and CD4 T cells. Positive associations existed between C3 and T cells, CD4 T cells, and CD8 T cells, whereas there was no significant correlation between C4 and lymphocyte subsets. PT was found positively correlated with IL6, IL8, and CRP. Reverse correlations were explored between C3, C4, and PT, CK-MB, total bilirubin. Conclusions: T cells, C3, and PT were identified as independent prognostic factors for mortality. Decreased C3 and C4, dysregulation of lymphocyte subsets and cytokines may lead to death after SARS-CoV-2 infection.


Asunto(s)
/epidemiología , Complemento C3/análisis , Citocinas/sangre , Subgrupos de Linfocitos T/inmunología , Anciano , Estudios de Casos y Controles , Comorbilidad , Femenino , Humanos , Hipertensión/complicaciones , Células Asesinas Naturales/inmunología , Recuento de Linfocitos , Linfopenia/patología , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo
12.
Science ; 371(6536): 1383-1388, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33766885

RESUMEN

αß and γδ T cell receptors (TCRs) are highly diverse antigen receptors that define two evolutionarily conserved T cell lineages. We describe a population of γµTCRs found exclusively in non-eutherian mammals that consist of a two-domain (Vγ-Cγ) γ-chain paired to a three-domain (Vµ-Vµj-Cµ) µ-chain. γµTCRs were characterized by restricted diversity in the Vγ and Vµj domains and a highly diverse unpaired Vµ domain. Crystal structures of two distinct γµTCRs revealed the structural basis of the association of the γµTCR heterodimer. The Vµ domain shared the characteristics of a single-domain antibody within which the hypervariable CDR3µ loop suggests a major antigen recognition determinant. We define here the molecular basis underpinning the assembly of a third TCR lineage, the γµTCR.


Asunto(s)
Monodelphis/inmunología , Receptores de Antígenos de Linfocitos T/química , Subgrupos de Linfocitos T/inmunología , Animales , Linaje de la Célula , Regiones Determinantes de Complementariedad/química , Cristalografía por Rayos X , Modelos Moleculares , Monodelphis/genética , Conformación Proteica , Dominios Proteicos , Multimerización de Proteína , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta , Receptores de Antígenos de Linfocitos T gamma-delta
13.
Nat Commun ; 12(1): 1921, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33771991

RESUMEN

Crohn's disease (CD) is a chronic transmural inflammation of intestinal segments caused by dysregulated interaction between microbiome and gut immune system. Here, we profile, via multiple single-cell technologies, T cells purified from the intestinal epithelium and lamina propria (LP) from terminal ileum resections of adult severe CD cases. We find that intraepithelial lymphocytes (IEL) contain several unique T cell subsets, including NKp30+γδT cells expressing RORγt and producing IL-26 upon NKp30 engagement. Further analyses comparing tissues from non-inflamed and inflamed regions of patients with CD versus healthy controls show increased activated TH17 but decreased CD8+T, γδT, TFH and Treg cells in inflamed tissues. Similar analyses of LP find increased CD8+, as well as reduced CD4+T cells with an elevated TH17 over Treg/TFH ratio. Our analyses of CD tissues thus suggest a potential link, pending additional validations, between transmural inflammation, reduced IEL γδT cells and altered spatial distribution of IEL and LP T cell subsets.


Asunto(s)
Enfermedad de Crohn/inmunología , Linfocitos Intraepiteliales/inmunología , Análisis de la Célula Individual/métodos , Subgrupos de Linfocitos T/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Células Cultivadas , Enfermedad de Crohn/patología , Perfilación de la Expresión Génica/métodos , Humanos , Linfocitos Intraepiteliales/metabolismo , Recuento de Linfocitos , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células Th17/inmunología , Células Th17/metabolismo
14.
Nat Commun ; 12(1): 1970, 2021 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-33785752

RESUMEN

Periods of fasting and refeeding may reduce cardiometabolic risk elevated by Western diet. Here we show in the substudy of NCT02099968, investigating the clinical parameters, the immunome and gut microbiome exploratory endpoints, that in hypertensive metabolic syndrome patients, a 5-day fast followed by a modified Dietary Approach to Stop Hypertension diet reduces systolic blood pressure, need for antihypertensive medications, body-mass index at three months post intervention compared to a modified Dietary Approach to Stop Hypertension diet alone. Fasting alters the gut microbiome, impacting bacterial taxa and gene modules associated with short-chain fatty acid production. Cross-system analyses reveal a positive correlation of circulating mucosa-associated invariant T cells, non-classical monocytes and CD4+ effector T cells with systolic blood pressure. Furthermore, regulatory T cells positively correlate with body-mass index and weight. Machine learning analysis of baseline immunome or microbiome data predicts sustained systolic blood pressure response within the fasting group, identifying CD8+ effector T cells, Th17 cells and regulatory T cells or Desulfovibrionaceae, Hydrogenoanaerobacterium, Akkermansia, and Ruminococcaceae as important contributors to the model. Here we report that the high-resolution multi-omics data highlight fasting as a promising non-pharmacological intervention for the treatment of high blood pressure in metabolic syndrome patients.


Asunto(s)
Presión Sanguínea/fisiología , Peso Corporal/fisiología , Ayuno/fisiología , Microbioma Gastrointestinal/fisiología , Síndrome Metabólico/fisiopatología , Anciano , Índice de Masa Corporal , Desulfovibrionaceae/fisiología , Dieta , Heces/microbiología , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/microbiología , Hipertensión/fisiopatología , Masculino , Síndrome Metabólico/complicaciones , Síndrome Metabólico/microbiología , Persona de Mediana Edad , Ruminococcus/fisiología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/fisiología
15.
Science ; 371(6535)2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33737460

RESUMEN

The intestine is a site of direct encounter with the external environment and must consequently balance barrier defense with nutrient uptake. To investigate how nutrient uptake is regulated in the small intestine, we tested the effect of diets with different macronutrient compositions on epithelial gene expression. We found that enzymes and transporters required for carbohydrate digestion and absorption were regulated by carbohydrate availability. The "on-demand" induction of this machinery required γδ T cells, which regulated this program through the suppression of interleukin-22 production by type 3 innate lymphoid cells. Nutrient availability altered the tissue localization and transcriptome of γδ T cells. Additionally, transcriptional responses to diet involved cellular remodeling of the epithelial compartment. Thus, this work identifies a role for γδ T cells in nutrient sensing.


Asunto(s)
Carbohidratos de la Dieta/administración & dosificación , Carbohidratos de la Dieta/metabolismo , Enterocitos/fisiología , Interleucinas/metabolismo , Mucosa Intestinal/fisiología , Receptores de Antígenos de Linfocitos T gamma-delta , Subgrupos de Linfocitos T/fisiología , Adaptación Fisiológica , Animales , Comunicación Celular , Proteínas en la Dieta/administración & dosificación , Digestión , Regulación de la Expresión Génica , Interleucinas/genética , Absorción Intestinal , Mucosa Intestinal/citología , Intestino Delgado/citología , Intestino Delgado/metabolismo , Ratones Endogámicos C57BL , Nutrientes/administración & dosificación , Nutrientes/metabolismo , Subgrupos de Linfocitos T/inmunología , Transcripción Genética , Transcriptoma
16.
Front Cell Infect Microbiol ; 11: 624483, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33718270

RESUMEN

The immune response type organized against viral infection is determinant in the prognosis of some infections. This work has aimed to study Th polarization in acute COVID-19 and its possible association with the outcome through an observational prospective study. Fifty-eight COVID-19 patients were recruited in the Medicine Department of the hospital "12 de Octubre," 55 patients remaining after losses to follow-up. Four groups were established according to maximum degree of disease progression. T-helper cell percentages and phenotypes, analyzed by flow cytometer, and serum cytokines levels, analyzed by Luminex, were evaluated when the microbiological diagnosis (acute phase) of the disease was obtained. Our study found a significant reduction of %Th1 and %Th17 cells with higher activated %Th2 cells in the COVID-19 patients compared with reference population. A higher percent of senescent Th2 cells was found in the patients who died than in those who survived. Senescent Th2 cell percentage was an independent risk factor for death (OR: 13.88) accompanied by the numbers of total lymphocytes (OR: 0.15) with an AUC of 0.879. COVID-19 patients showed a profile of pro-inflammatory serum cytokines compared to controls, with higher levels of IL-2, IL-6, IL-15, and IP-10. IL-10 and IL-13 were also elevated in patients compared to controls. Patients who did not survive presented significantly higher levels of IL-15 than those who recovered. No significant differences were observed according to disease progression groups. The study has shown that increased levels of IL-15 and a high Th2 response are associated with a fatal outcome of the disease.


Asunto(s)
/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Adulto , Anciano , /patología , Citocinas/sangre , Progresión de la Enfermedad , Femenino , Humanos , Inmunidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Prospectivos , Células TH1/inmunología , Células Th17/inmunología , Células Th2/inmunología
17.
Arch Immunol Ther Exp (Warsz) ; 69(1): 4, 2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33661375

RESUMEN

A minor subset (approximately 5%) of peripheral T cells has their TCR build up from γ and δ chains instead of α and ß-those are the γδ T lymphocytes. They can be functionally divided into subsets, e.g., Th1-, Th2-, Th9-, Th17-, Tfh-, and Treg-like γδ T cells. They share some specifics of both innate and adaptive immunity, and are capable of rapid response to a range of stimuli, including some viral and bacterial infections. Atopic diseases, including asthma, are one of major health-related problems of modern western societies. Asthma is one of the most common airway diseases, affecting people of all ages and having potential life-threatening consequences. In this paper, we review the current knowledge about the involvement of γδ T cells in the pathogenesis of asthma and its exacerbations. We summarize both the studies performed on human subjects as well as on the murine model of asthma. γδ T cells seem to be involved in the pathogenesis of asthma, different subsets probably perform opposite functions, e.g., symptom-exacerbating Vγ1 and symptom-suppressing Vγ4 in mice model of asthma.


Asunto(s)
Asma/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/fisiología , Subgrupos de Linfocitos T/inmunología , Animales , Asma/etiología , Humanos , Inmunoglobulina E/sangre , Interferón gamma/fisiología , Interleucina-17/biosíntesis , Ratones , Hipersensibilidad Respiratoria/inmunología , Células Th2/inmunología
18.
Nat Commun ; 12(1): 1446, 2021 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-33664261

RESUMEN

Invariant natural killer T cells (iNKT cells) differentiate into thymic and peripheral NKT1, NKT2 and NKT17 subsets. Here we use RNA-seq and ATAC-seq analyses and show iNKT subsets are similar, regardless of tissue location. Lung iNKT cell subsets possess the most distinct location-specific features, shared with other innate lymphocytes in the lung, possibly consistent with increased activation. Following antigenic stimulation, iNKT cells undergo chromatin and transcriptional changes delineating two populations: one similar to follicular helper T cells and the other NK or effector like. Phenotypic analysis indicates these changes are observed long-term, suggesting that iNKT cells gene programs are not fixed, but they are capable of chromatin remodeling after antigen to give rise to additional subsets.


Asunto(s)
Pulmón/citología , Células T Asesinas Naturales/citología , Subgrupos de Linfocitos T/citología , Timo/citología , Animales , Diferenciación Celular/inmunología , Cromatina/genética , Femenino , Pulmón/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células T Asesinas Naturales/inmunología , Subgrupos de Linfocitos T/inmunología , Timo/inmunología , Transcriptoma/genética
19.
Immunity ; 54(3): 542-556.e9, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33631118

RESUMEN

A combination of vaccination approaches will likely be necessary to fully control the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Here, we show that modified vaccinia Ankara (MVA) vectors expressing membrane-anchored pre-fusion stabilized spike (MVA/S) but not secreted S1 induced strong neutralizing antibody responses against SARS-CoV-2 in mice. In macaques, the MVA/S vaccination induced strong neutralizing antibodies and CD8+ T cell responses, and conferred protection from SARS-CoV-2 infection and virus replication in the lungs as early as day 2 following intranasal and intratracheal challenge. Single-cell RNA sequencing analysis of lung cells on day 4 after infection revealed that MVA/S vaccination also protected macaques from infection-induced inflammation and B cell abnormalities and lowered induction of interferon-stimulated genes. These results demonstrate that MVA/S vaccination induces neutralizing antibodies and CD8+ T cells in the blood and lungs and is a potential vaccine candidate for SARS-CoV-2.


Asunto(s)
/inmunología , Vectores Genéticos/genética , Vacunas de ADN/inmunología , Virus Vaccinia/genética , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Antígenos Virales/genética , Antígenos Virales/inmunología , /patología , /genética , Modelos Animales de Enfermedad , Expresión Génica , Orden Génico , Inmunofenotipificación , Pulmón/inmunología , Pulmón/patología , Pulmón/virología , Macaca , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patología , Ratones , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Vacunación/métodos , Vacunas de ADN/genética
20.
J Exp Med ; 218(4)2021 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-33533915

RESUMEN

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


Asunto(s)
/inmunología , Interacciones Huésped-Patógeno/inmunología , Inmunidad Celular , /inmunología , Adulto , Anciano , Antígenos Virales/inmunología , Biomarcadores , Femenino , Humanos , Inmunofenotipificación , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Especificidad del Receptor de Antígeno de Linfocitos T , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Adulto Joven
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