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1.
Science ; 372(6537)2021 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-33795428

RESUMEN

T cell exhaustion limits immune responses against cancer and is a major cause of resistance to chimeric antigen receptor (CAR)-T cell therapeutics. Using murine xenograft models and an in vitro model wherein tonic CAR signaling induces hallmark features of exhaustion, we tested the effect of transient cessation of receptor signaling, or rest, on the development and maintenance of exhaustion. Induction of rest through enforced down-regulation of the CAR protein using a drug-regulatable system or treatment with the multikinase inhibitor dasatinib resulted in the acquisition of a memory-like phenotype, global transcriptional and epigenetic reprogramming, and restored antitumor functionality in exhausted CAR-T cells. This work demonstrates that rest can enhance CAR-T cell efficacy by preventing or reversing exhaustion, and it challenges the notion that exhaustion is an epigenetically fixed state.


Asunto(s)
Dasatinib/farmacología , Epigénesis Genética , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T/inmunología , Animales , Línea Celular Tumoral , Citotoxicidad Inmunológica , Regulación hacia Abajo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Epigenoma , Femenino , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Proteínas del Grupo de Alta Movilidad/metabolismo , Humanos , Memoria Inmunológica , Activación de Linfocitos , Factor de Unión 1 al Potenciador Linfoide/metabolismo , Masculino , Ratones , Neoplasias Experimentales/terapia , Dominios Proteicos , Estabilidad Proteica , Receptores Quiméricos de Antígenos/química , Receptores Quiméricos de Antígenos/inmunología , Transducción de Señal , Linfocitos T/metabolismo , Transcripción Genética , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Nat Commun ; 12(1): 2133, 2021 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-33837219

RESUMEN

Our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still developing. We perform an observational study to investigate seroprevalence and immune responses in subjects professionally exposed to SARS-CoV-2 and their family members (155 individuals; ages 5-79 years). Seropositivity for SARS-CoV-2 Spike glycoprotein aligns with PCR results that confirm the previous infection. Anti-Spike IgG/IgM titers remain high 60 days post-infection and do not strongly associate with symptoms, except for fever. We analyze PBMCs from a subset of seropositive and seronegative adults. TLR7 agonist-activation reveals an increased population of IL-6+TNF-IL-1ß+ monocytes, while SARS-CoV-2 peptide stimulation elicits IL-33, IL-6, IFNa2, and IL-23 expression in seropositive individuals. IL-33 correlates with CD4+ T cell activation in PBMCs from convalescent subjects and is likely due to T cell-mediated effects on IL-33-producing cells. IL-33 is associated with pulmonary infection and chronic diseases like asthma and COPD, but its role in COVID-19 is unknown. Analysis of published scRNAseq data of bronchoalveolar lavage fluid (BALF) from patients with mild to severe COVID-19 reveals a population of IL-33-producing cells that increases with the disease. Together these findings show that IL-33 production is linked to SARS-CoV-2 infection and warrant further investigation of IL-33 in COVID-19 pathogenesis and immunity.


Asunto(s)
Anticuerpos Antivirales/inmunología , Inmunoglobulina G/inmunología , Interleucina-33/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Interleucina-33/metabolismo , Masculino , Persona de Mediana Edad , /fisiología , Estudios Seroepidemiológicos , Glicoproteína de la Espiga del Coronavirus/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo , Adulto Joven
3.
Int J Mol Sci ; 22(5)2021 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-33800462

RESUMEN

Human CD137 (4-1BB), a member of the TNF receptor family, and its ligand CD137L (4-1BBL), are expressed on immune cells and tumor cells. CD137/CD137L interaction mediates bidirectional cellular responses of potential relevance in inflammatory diseases, autoimmunity and oncology. A soluble form of CD137 exists, elevated levels of which have been reported in patients with rheumatoid arthritis and various malignancies. Soluble CD137 (sCD137) is considered to represent a splice variant of CD137. In this report, however, evidence is presented that A Disintegrin and Metalloproteinase (ADAM)10 and potentially also ADAM17 are centrally involved in its generation. Release of sCD137 by transfected cell lines and primary T cells was uniformly inhibitable by ADAM10 inhibition. The shedding function of ADAM10 can be blocked through inhibition of its interaction with surface exposed phosphatidylserine (PS), and this effectively inhibited sCD137 generation. The phospholipid scramblase Anoctamin-6 (ANO6) traffics PS to the outer membrane and thus modifies ADAM10 function. Overexpression of ANO6 increased stimulated shedding, and hyperactive ANO6 led to maximal constitutive shedding of CD137. sCD137 was functionally active and augmented T cell proliferation. Our findings shed new light on the regulation of CD137/CD137L immune responses with potential impact on immunotherapeutic approaches targeting CD137.


Asunto(s)
Proteína ADAM10/metabolismo , Proteína ADAM17/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Artritis Reumatoide/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Anoctaminas/metabolismo , Artritis Reumatoide/patología , Membrana Celular/metabolismo , Células HEK293 , Células HT29 , Humanos , Neoplasias/patología , Proteínas de Transferencia de Fosfolípidos/metabolismo , Linfocitos T/metabolismo , Linfocitos T/patología
4.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33802979

RESUMEN

Patients with ulcerative colitis (UC) have reduced intestinal levels of short-chain fatty acids (SCFAs), including butyrate, which are important regulators of host-microbiota crosstalk. The aim was therefore to determine effects of butyrate on blood and intestinal T cells from patients with active UC. T cells from UC patients and healthy subjects were polyclonally stimulated together with SCFAs and proliferation, activation, cytokine secretion, and surface expression of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) were analyzed. Butyrate induced comparable, dose dependent inhibition of activation and proliferation in blood T cells and activation in intestinal T cells from UC patients and healthy subjects. However, surface expression of the inhibitory molecule CTLA-4 on stimulated blood and intestinal T cells was impaired in UC patients and was not restored following butyrate treatment. Furthermore, unlike intestinal T cells from healthy subjects, butyrate was unable to downregulate secretion of interferon gamma (IFNγ), interleukin (IL)-4, IL-17A, and IL-10 in UC patients. Although seemingly normal inhibitory effects on T cell activation and proliferation, butyrate has an impaired ability to reduce cytokine secretion and induce surface expression of CTLA-4 in T cells from UC patients with active disease. Overall, these observations indicate a dysfunction in butyrate induced immune regulation linked to CTLA-4 signaling in T cells from UC patients during a flare.


Asunto(s)
Antígeno CTLA-4/metabolismo , Colitis Ulcerosa/inmunología , Linfocitos T/metabolismo , Adulto , Anciano , Proliferación Celular/efectos de los fármacos , Colitis Ulcerosa/sangre , Colitis Ulcerosa/patología , Citocinas/metabolismo , Citotoxicidad Inmunológica/efectos de los fármacos , Femenino , Humanos , Inflamación/patología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Activación de Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Adulto Joven
5.
Anticancer Res ; 41(4): 1811-1819, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813386

RESUMEN

BACKGROUND/AIM: Glioblastoma is the most common cancer among primary brain tumors, however, its prognosis and treatment advances are very poor. Here, we investigated whether c-Met, FOLR1, and AXL proteins are promising targets for chimeric antigen receptor (CAR) T-cell therapy, for they are known to be over-expressed in a variety of solid tumors. MATERIALS AND METHODS: CAR constructs were prepared and CAR KHYG-1 cells targeting c-Met, FOLR1, or AXL were made by lentiviral transduction. The activity of CAR KHYG-1 cells against cancer cells was measured by cytokine secretion and cell lysis assays. RESULTS: c-Met and AXL were over-expressed in most glioblastoma cell lines (11/13), but not in neuroblastoma cell lines (0/8). FOLR1 was over-expressed only in one among 16 glioblastoma cell lines. Our antigen-specific CAR KHYG-1 cells eradicated target positive glioblastoma cells selectively. CONCLUSION: Anti-c-Met and anti-AXL CAR NK or T cells could be effective in glioblastoma cells.


Asunto(s)
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Inmunoterapia Adoptiva , Células Asesinas Naturales/inmunología , Proteínas Proto-Oncogénicas c-met/inmunología , Proteínas Proto-Oncogénicas/inmunología , Proteínas Tirosina Quinasas Receptoras/inmunología , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/inmunología , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Técnicas de Cocultivo , Citocinas/metabolismo , Citotoxicidad Inmunológica , Receptor 1 de Folato/inmunología , Receptor 1 de Folato/metabolismo , Glioblastoma/inmunología , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Células Jurkat , Células Asesinas Naturales/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T/metabolismo
6.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33806895

RESUMEN

Skeletal muscle regeneration is highly dependent on the inflammatory response. A wide variety of innate and adaptive immune cells orchestrate the complex process of muscle repair. This review provides information about the various types of immune cells and biomolecules that have been shown to mediate muscle regeneration following injury and degenerative diseases. Recently developed cell and drug-based immunomodulatory strategies are highlighted. An improved understanding of the immune response to injured and diseased skeletal muscle will be essential for the development of therapeutic strategies.


Asunto(s)
Inmunidad Adaptativa , Inmunidad Innata , Músculo Esquelético/fisiología , Regeneración/inmunología , Factores de Edad , Animales , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Susceptibilidad a Enfermedades , Humanos , Inmunomodulación , Leucocitos/inmunología , Leucocitos/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Desarrollo de Músculos/genética , Desarrollo de Músculos/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo
7.
Methods Mol Biol ; 2265: 305-321, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33704724

RESUMEN

Tumor-derived exosomes (TEX), a subset of small extracellular vesicles (EVs) which originate from the endocytic compartment of tumor cells, are emerging as key players in cancer progression. TEX circulate freely in patients' body fluids and transfer bioactive cargos from tumor to various recipient cells. The molecular cargo of melanoma cell-derived exosomes (MTEX) mimics that of the tumor, and MTEX serve as a liquid biopsy that provides potentially useful information for cancer diagnosis, prognosis, or responses to therapy. Plasma of melanoma patients contains a mix of MTEX and exosomes produced by nonmalignant cells (NMTEX). Isolation of these exosome subtypes from the bulk of plasma exosomes is necessary to evaluate contributions of each as potential biomarkers of melanoma progression and outcome. Here, methods for separation of MTEX from T cell-derived exosomes from a single small volume of plasma and their subsequent molecular and functional characterization are described. Following size exclusion chromatography (SEC) to isolate total plasma exosomes, immune affinity-based capture of MTEX with anti-CSPG4 antibody and then of exosomes produced by T cells with anti-CD3 antibody is used to sequentially isolate the two subsets. This immune capture method enables the recovery of MTEX and CD3+ exosomes in quantities sufficient both for molecular profiling by flow cytometry or western blotting and for functional analyses.


Asunto(s)
Biomarcadores de Tumor/sangre , Western Blotting , Exosomas/metabolismo , Citometría de Flujo , Melanoma/sangre , Linfocitos T/metabolismo , Cromatografía en Gel , Exosomas/patología , Humanos , Biopsia Líquida , Plasma/metabolismo , Linfocitos T/patología
8.
Medicine (Baltimore) ; 100(12): e25157, 2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33761687

RESUMEN

BACKGROUND: As immune checkpoint pathways, programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) can be exploited by tumor cells to evade immuno-surveillance. Inflammation and immune processes play decisive roles in the occurrence and development of coronary heart disease (CHD). The low expression level of PD-1/ PD-L1 or anti-PD-1/PD-L1 therapy can accelerate the immune processes in CHD and aggravates disease based on numerous studies. However, the expression of PD-L1 and CHD still remains controversial to date. We conducted this meta-analysis to detect the value of PD-L1 expression on peripheral T-cells in CHD. METHODS: We will search PubMed, Embase, Web of Science, Google Scholar, Chinese National Knowledge Infrastructure, Chinese VIP Information, Wanfang Database, and Chinese Biomedical Literature Database for related published studies before February 2021. Two review authors will search and assess relevant studies independently. Case control studies and cohort studies will be included. The Revman 5.3 software was applied to carry out the meta-analysis for the included literature. RESULTS: The findings of this systematic review will be disseminated in a peer-reviewed publication and/or presented at relevant conferences. CONCLUSION: This study will provide a new theoretical basis for the immunological prevention and treatment of CHD. TRIAL REGISTRATION NUMBER: DOI 10.17605/OSF.IO/X3R52. ETHICS AND DISSEMINATION: Formal ethical approval is not required, as the data are not individualized.


Asunto(s)
Antígeno B7-H1/metabolismo , Enfermedad Coronaria/inmunología , Metaanálisis como Asunto , Revisiones Sistemáticas como Asunto , Linfocitos T/metabolismo , Enfermedad Coronaria/terapia , Humanos , Proyectos de Investigación
9.
Nat Commun ; 12(1): 1916, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33772022

RESUMEN

Multiphoton microscopy is a powerful technique for deep in vivo imaging in scattering samples. However, it requires precise, sample-dependent increases in excitation power with depth in order to generate contrast in scattering tissue, while minimizing photobleaching and phototoxicity. We show here how adaptive imaging can optimize illumination power at each point in a 3D volume as a function of the sample's shape, without the need for specialized fluorescent labeling. Our method relies on training a physics-based machine learning model using cells with identical fluorescent labels imaged in situ. We use this technique for in vivo imaging of immune responses in mouse lymph nodes following vaccination. We achieve visualization of physiologically realistic numbers of antigen-specific T cells (~2 orders of magnitude lower than previous studies), and demonstrate changes in the global organization and motility of dendritic cell networks during the early stages of the immune response. We provide a step-by-step tutorial for implementing this technique using exclusively open-source hardware and software.


Asunto(s)
Inmunidad/inmunología , Ganglios Linfáticos/inmunología , Microscopía de Fluorescencia por Excitación Multifotónica/métodos , Vacunación/métodos , Inmunidad Adaptativa/inmunología , Algoritmos , Animales , Antígenos/inmunología , Femenino , Ganglios Linfáticos/metabolismo , Aprendizaje Automático , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía de Fluorescencia por Excitación Multifotónica/instrumentación , Linfocitos T/inmunología , Linfocitos T/metabolismo
10.
Cell Prolif ; 54(4): e13022, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33686740

RESUMEN

OBJECTIVES: This study aimed to investigate the protective effect of SCARF1 on acute rejection (AR), phagocytic clearance of Kupffer cells (KCs), M2 polarization and the exact mechanism underlying these processes. METHODS: AAV was transfected into the portal vein of rats, and AR and immune tolerance (IT) models of liver transplantation were established. Liver tissue and blood samples were collected. The level of SCARF1 was detected via WB and immunohistochemical staining. Pathological changes in liver tissue were detected using HE staining. Apoptotic cells were detected using TUNEL staining. KC polarization was assessed via immunohistochemical staining. Primary KCs were isolated and co-cultured with apoptotic T lymphocytes. Phagocytosis of apoptotic cells and polarization of KCs were both detected using immunofluorescence. Calcium concentration was determined using immunofluorescence and a fluorescence microplate reader. The levels of PI3K, p-AKT and P-STAT3 were assessed via WB and immunofluorescence. RESULTS: Compared to the IT group, the level of SCARF1 was significantly decreased in the AR group. Overexpression of SCARF1 in KCs improved AR and liver function markers. Enhanced phagocytosis mediated by SCARF1 is beneficial for improving the apoptotic clearance of AR and promoting M2 polarization of KCs. SCARF1-mediated enhancement of phagocytosis promotes increased calcium concentration in KCs, thus further activating the PI3K-AKT-STAT3 signalling pathway. CONCLUSIONS: SCARF1 promotes the M2 polarization of KCs by promoting phagocytosis through the calcium-dependent PI3K-AKT-STAT3 signalling pathway.


Asunto(s)
Calcio/metabolismo , Trasplante de Hígado , Receptores Depuradores de Clase F/metabolismo , Transducción de Señal , Animales , Apoptosis , Polaridad Celular , Células Cultivadas , Técnicas de Cocultivo , Macrófagos del Hígado/citología , Macrófagos del Hígado/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Fagocitosis , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Endogámicas Lew , Factor de Transcripción STAT3/metabolismo , Receptores Depuradores de Clase F/genética , Linfocitos T/citología , Linfocitos T/metabolismo
11.
Nat Commun ; 12(1): 1455, 2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33674593

RESUMEN

T-cell exhaustion denotes a hypofunctional state of T lymphocytes commonly found in cancer, but how tumor cells drive T-cell exhaustion remains elusive. Here, we find T-cell exhaustion linked to overall survival in 675 hepatocellular carcinoma (HCC) patients with diverse ethnicities and etiologies. Integrative omics analyses uncover oncogenic reprograming of HCC methionine recycling with elevated 5-methylthioadenosine (MTA) and S-adenosylmethionine (SAM) to be tightly linked to T-cell exhaustion. SAM and MTA induce T-cell dysfunction in vitro. Moreover, CRISPR-Cas9-mediated deletion of MAT2A, a key SAM producing enzyme, results in an inhibition of T-cell dysfunction and HCC growth in mice. Thus, reprogramming of tumor methionine metabolism may be a viable therapeutic strategy to improve HCC immunity.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Metionina/metabolismo , Linfocitos T/metabolismo , Animales , Biomarcadores de Tumor , Linfocitos T CD8-positivos , Sistemas CRISPR-Cas , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Inactivación de Genes , Humanos , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Metionina Adenosiltransferasa/sangre , Metionina Adenosiltransferasa/genética , Metionina Adenosiltransferasa/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , S-Adenosilmetionina/metabolismo , Transcriptoma
12.
Int J Mol Sci ; 22(4)2021 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-33672997

RESUMEN

The Philadelphia-negative myeloproliferative neoplasms (MPNs) are malignancies of the hematopoietic stem cell (HSC) arising as a consequence of clonal proliferation driven by somatically acquired driver mutations in discrete genes (JAK2, CALR, MPL). In recent years, along with the advances in molecular characterization, the role of immune dysregulation has been achieving increasing relevance in the pathogenesis and evolution of MPNs. In particular, a growing number of studies have shown that MPNs are often associated with detrimental cytokine milieu, expansion of the monocyte/macrophage compartment and myeloid-derived suppressor cells, as well as altered functions of T cells, dendritic cells and NK cells. Moreover, akin to solid tumors and other hematological malignancies, MPNs are able to evade T cell immune surveillance by engaging the PD-1/PD-L1 axis, whose pharmacological blockade with checkpoint inhibitors can successfully restore effective antitumor responses. A further interesting cue is provided by the recent discovery of the high immunogenic potential of JAK2V617F and CALR exon 9 mutations, that could be harnessed as intriguing targets for innovative adoptive immunotherapies. This review focuses on the recent insights in the immunological dysfunctions contributing to the pathogenesis of MPNs and outlines the potential impact of related immunotherapeutic approaches.


Asunto(s)
Células Madre Hematopoyéticas/inmunología , Inmunoterapia/métodos , Inflamación/inmunología , Trastornos Mieloproliferativos/terapia , Linfocitos T/inmunología , Microambiente Tumoral/inmunología , Calreticulina/genética , Calreticulina/inmunología , Calreticulina/metabolismo , Células Madre Hematopoyéticas/metabolismo , Humanos , Inflamación/genética , Janus Quinasa 2/genética , Janus Quinasa 2/inmunología , Janus Quinasa 2/metabolismo , Mutación/inmunología , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/inmunología , Cromosoma Filadelfia , Linfocitos T/metabolismo , Microambiente Tumoral/genética
13.
Nat Commun ; 12(1): 1930, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33772027

RESUMEN

In our clinical trials of oncolytic vesicular stomatitis virus expressing interferon beta (VSV-IFNß), several patients achieved initial responses followed by aggressive relapse. We show here that VSV-IFNß-escape tumors predictably express a point-mutated CSDE1P5S form of the RNA-binding Cold Shock Domain-containing E1 protein, which promotes escape as an inhibitor of VSV replication by disrupting viral transcription. Given time, VSV-IFNß evolves a compensatory mutation in the P/M Inter-Genic Region which rescues replication in CSDE1P5S cells. These data show that CSDE1 is a major cellular co-factor for VSV replication. However, CSDE1P5S also generates a neo-epitope recognized by non-tolerized T cells. We exploit this predictable neo-antigenesis to drive, and trap, tumors into an escape phenotype, which can be ambushed by vaccination against CSDE1P5S, preventing tumor escape. Combining frontline therapy with escape-targeting immunotherapy will be applicable across multiple therapies which drive tumor mutation/evolution and simultaneously generate novel, targetable immunopeptidomes associated with acquired treatment resistance.


Asunto(s)
Proteínas de Unión al ADN/inmunología , Interferón beta/inmunología , Viroterapia Oncolítica/métodos , Virus Oncolíticos/inmunología , Proteínas de Unión al ARN/inmunología , Virus de la Estomatitis Vesicular Indiana/inmunología , Replicación Viral/inmunología , Animales , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/inmunología , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Inmunoterapia/métodos , Interferón beta/metabolismo , Ratones Endogámicos C57BL , Mutación , Virus Oncolíticos/metabolismo , Virus Oncolíticos/fisiología , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Virus de la Estomatitis Vesicular Indiana/metabolismo , Virus de la Estomatitis Vesicular Indiana/fisiología
14.
Mol Pharmacol ; 99(5): 370-382, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33674363

RESUMEN

Prostaglandin E2 (PGE2) is a key lipid mediator in health and disease and serves as a crucial link between the immune response and cancer. With the advent of cancer therapies targeting PGE2 signaling pathways at different levels, there has been increased interest in mapping and understanding the complex and interconnected signaling pathways arising from the four distinct PGE2 receptors. Here, we review phosphoproteomics studies that have investigated different aspects of PGE2 signaling in T cells. These studies have elucidated PGE2's regulatory effect on T cell receptor signaling and T cell function, the key role of protein kinase A in many PGE2 signaling pathways, the temporal regulation of PGE2 signaling, differences in PGE2 signaling between different T cell subtypes, and finally, the crosstalk between PGE2 signaling pathways elicited by the four distinct PGE2 receptors present in T cells. SIGNIFICANCE STATEMENT: Through the reviewed studies, we now have a much better understanding of PGE2's signaling mechanisms and functional roles in T cells, as well as a solid platform for targeted and functional studies of specific PGE2-triggered pathways in T cells.


Asunto(s)
Dinoprostona/metabolismo , Fosforilación/fisiología , Proteoma/metabolismo , Transducción de Señal/fisiología , Linfocitos T/metabolismo , Humanos , Proteómica/métodos
15.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33669065

RESUMEN

Immunosenescence is characterized by age-associated changes in immunological functions. Although age- and autoimmune-related sialadenitis cause dry mouth (xerostomia), the roles of immunosenescence and cellular senescence in the pathogenesis of sialadenitis remain unknown. We demonstrated that acquired immune cells rather than innate immune cells infiltrated the salivary glands (SG) of aged mice. An analysis of isolated epithelial cells from SG revealed that the expression levels of the chemokine CXCL13 were elevated in aged mice. Senescence-associated T cells (SA-Ts), which secrete large amounts of atypical pro-inflammatory cytokines, are involved in the pathogenesis of metabolic disorders and autoimmune diseases. The present results showed that SA-Ts and B cells, which express the CXCL13 receptor CXCR5, accumulated in the SG of aged mice, particularly females. CD4+ T cells derived from aged mice exhibited stronger in vitro migratory activity toward CXCL13 than those from young mice. In a mouse model of Sjögren's syndrome (SS), SA-Ts also accumulated in SG, presumably via CXCL12-CXCR4 signaling. Collectively, the present results indicate that SA-Ts accumulate in SG, contribute to the pathogenesis of age- and SS-related sialadenitis by up-regulating chemokines in epithelial cells, and have potential as therapeutic targets for the treatment of xerostomia caused by these types of sialadenitis.


Asunto(s)
Senescencia Celular/inmunología , Quimiocinas/metabolismo , Células Epiteliales/metabolismo , Glándulas Salivales/metabolismo , Sialadenitis/metabolismo , Síndrome de Sjögren/inmunología , Linfocitos T/metabolismo , Xerostomía/metabolismo , Animales , Enfermedades Autoinmunes/metabolismo , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Movimiento Celular/inmunología , Quimiocina CXCL13/genética , Quimiocina CXCL13/metabolismo , Quimiocinas/genética , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Glándulas Salivales/citología , Glándulas Salivales/inmunología , Sialadenitis/patología , Síndrome de Sjögren/patología , Linfocitos T/inmunología , Xerostomía/patología
16.
Front Immunol ; 12: 655934, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33777054

RESUMEN

COVID-19 manifests with a wide diversity of clinical phenotypes characterized by dysfunctional and exaggerated host immune responses. Many results have been described on the status of the immune system of patients infected with SARS-CoV-2, but there are still aspects that have not been fully characterized or understood. In this study, we have analyzed a cohort of patients with mild, moderate and severe disease. We performed flow cytometric studies and correlated the data with the clinical characteristics and clinical laboratory values of the patients. Both conventional and unsupervised data analyses concluded that patients with severe disease are characterized, among others, by a higher state of activation in all T cell subsets (CD4, CD8, double negative and T follicular helper cells), higher expression of perforin and granzyme B in cytotoxic cells, expansion of adaptive NK cells and the accumulation of activated and immature dysfunctional monocytes which are identified by a low expression of HLA-DR and an intriguing shift in the expression pattern of CD300 receptors. More importantly, correlation analysis showed a strong association between the alterations in the immune cells and the clinical signs of severity. These results indicate that patients with severe COVID-19 have a broad perturbation of their immune system, and they will help to understand the immunopathogenesis of COVID-19.


Asunto(s)
/inmunología , Citotoxicidad Inmunológica , Células Asesinas Naturales/inmunología , Activación de Linfocitos , Monocitos/inmunología , Receptores Inmunológicos/sangre , Linfocitos T/inmunología , Anciano , /diagnóstico , Estudios de Casos y Controles , Estudios Transversales , Femenino , Citometría de Flujo , Interacciones Huésped-Patógeno , Humanos , Inmunofenotipificación , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/virología , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Monocitos/virología , Fenotipo , Índice de Severidad de la Enfermedad , Linfocitos T/metabolismo , Linfocitos T/virología
17.
J Exp Med ; 218(5)2021 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-33646265

RESUMEN

The efficacy of virus-specific T cells in clearing pathogens involves a fine balance between antiviral and inflammatory features. SARS-CoV-2-specific T cells in individuals who clear SARS-CoV-2 without symptoms could reveal nonpathological yet protective characteristics. We longitudinally studied SARS-CoV-2-specific T cells in a cohort of asymptomatic (n = 85) and symptomatic (n = 75) COVID-19 patients after seroconversion. We quantified T cells reactive to structural proteins (M, NP, and Spike) using ELISpot and cytokine secretion in whole blood. Frequencies of SARS-CoV-2-specific T cells were similar between asymptomatic and symptomatic individuals, but the former showed an increased IFN-γ and IL-2 production. This was associated with a proportional secretion of IL-10 and proinflammatory cytokines (IL-6, TNF-α, and IL-1ß) only in asymptomatic infection, while a disproportionate secretion of inflammatory cytokines was triggered by SARS-CoV-2-specific T cell activation in symptomatic individuals. Thus, asymptomatic SARS-CoV-2-infected individuals are not characterized by weak antiviral immunity; on the contrary, they mount a highly functional virus-specific cellular immune response.


Asunto(s)
Infecciones Asintomáticas , Citocinas/inmunología , Activación de Linfocitos , Linfocitos T/inmunología , Adulto , Citocinas/sangre , Humanos , Masculino , Persona de Mediana Edad , Linfocitos T/metabolismo
18.
Cell Rep ; 34(11): 108863, 2021 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-33691089

RESUMEN

It is unclear why some SARS-CoV-2 patients readily resolve infection while others develop severe disease. By interrogating metabolic programs of immune cells in severe and recovered coronavirus disease 2019 (COVID-19) patients compared with other viral infections, we identify a unique population of T cells. These T cells express increased Voltage-Dependent Anion Channel 1 (VDAC1), accompanied by gene programs and functional characteristics linked to mitochondrial dysfunction and apoptosis. The percentage of these cells increases in elderly patients and correlates with lymphopenia. Importantly, T cell apoptosis is inhibited in vitro by targeting the oligomerization of VDAC1 or blocking caspase activity. We also observe an expansion of myeloid-derived suppressor cells with unique metabolic phenotypes specific to COVID-19, and their presence distinguishes severe from mild disease. Overall, the identification of these metabolic phenotypes provides insight into the dysfunctional immune response in acutely ill COVID-19 patients and provides a means to predict and track disease severity and/or design metabolic therapeutic regimens.


Asunto(s)
/inmunología , Inmunidad/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/inmunología , Caspasas/inmunología , Caspasas/metabolismo , Femenino , Humanos , Linfopenia/inmunología , Linfopenia/metabolismo , Masculino , Persona de Mediana Edad , Mitocondrias/inmunología , Mitocondrias/metabolismo , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Canal Aniónico 1 Dependiente del Voltaje/metabolismo , Adulto Joven
19.
Adv Exp Med Biol ; 1316: 149-167, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33740249

RESUMEN

T cells recognize "foreign" antigens and induce durable humoral and cellular immune responses, which are indispensable for defending pathogens, as well as maintaining the integrity and homeostasis of tissues and organs. T cells are the major immune cell population in the tumor microenvironment which play a critical role in the antitumor immune response and cancer immune surveillance. Defective immune response of tumor-infiltrating T cells is the main cause of cancer immune evasion. The antitumor response of T cells is affected by multiple factors in the tumor microenvironment, including immunosuppressive cells, immune inhibitory cytokines, tumor-derived suppressive signals like PD-L1, immnuogenicity of tumor cells, as well as metabolic factors like hypoxia and nutrient deprivation. Abundant studies in past decades have proved the metabolic regulations of the immune response of T cells and the tumor-infiltrating T cells. In this chapter, we will discuss the regulations of the antitumor response of tumor-infiltrating T cells by lipid metabolism, which is one of the main components of metabolic regulation.


Asunto(s)
Neoplasias , Linfocitos T , Citocinas/metabolismo , Humanos , Metabolismo de los Lípidos , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos T/metabolismo , Microambiente Tumoral
20.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33673033

RESUMEN

T-cell clonality testing is integral to the diagnostic work-up of T-cell malignancies; however, current methods lack specificity and sensitivity, which can make the diagnostic process difficult. The recent discovery of a monoclonal antibody (mAb) specific for human TRBC1 will greatly improve the outlook for T-cell malignancy diagnostics. The anti-TRBC1 mAb can be used in flow cytometry immunophenotyping assays to provide a low-cost, robust, and highly specific test that detects clonality of immunophenotypically distinct T-cell populations. Recent studies demonstrate the clinical utility of this approach in several contexts; use of this antibody in appropriately designed flow cytometry panels improves detection of circulating disease in patients with cutaneous T-cell lymphoma, eliminates the need for molecular clonality testing in the context of large granular lymphocyte leukemia, and provides more conclusive results in the context of many other T-cell disorders. It is worth noting that the increased ability to detect discrete clonal T-cell populations means that identification of T-cell clones of uncertain clinical significance (T-CUS) will become more common. This review discusses this new antibody and describes how it defines clonal T-cells. We present and discuss assay design and summarize findings to date about the use of flow cytometry TRBC1 analysis in the field of diagnostics, including lymph node and fluid sample investigations. We also make suggestions about how to apply the assay results in clinical work-ups, including how to interpret and report findings of T-CUS. Finally, we highlight areas that we think will benefit from further research.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Linfoma de Células T , Proteínas de Neoplasias/biosíntesis , Receptores de Antígenos de Linfocitos T alfa-beta/biosíntesis , Linfocitos T/metabolismo , Humanos , Linfoma de Células T/diagnóstico , Linfoma de Células T/metabolismo , Linfoma de Células T/patología , Linfocitos T/patología
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