scholarly journals The P2X7 Receptor in Tumor Immunity

2021 ◽  
Vol 9 ◽  
Author(s):  
Fabio Grassi ◽  
Benedetta De Ponte Conti
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
T Cell ◽  
P2x7 Receptor ◽  
Tissue Repair ◽  
Innate Immune ◽  
Tumor Control ◽  
Extracellular Adenosine ◽  
Molecular Pattern ◽  
Cell Immunity

Extracellular adenosine triphosphate (eATP) is a potent mediator of the immune response via stimulation of purinergic P2 receptors. ATP concentration in the extracellular space increases dramatically during tissue damage and eATP acts as a danger-associated molecular pattern (DAMP) to alert innate immune system cells for tissue repair. Similarly, eATP is present at hundreds of micromolar concentration in the tumor microenvironment (TME). However, its impact on antitumor immune response is still not well established, probably because of the complexity of the responses it induces in different cells constituting the TME. On one hand, ATP released by tumor cells concomitantly to cell death can contribute to immunogenic cell death (ICD) that is proinflammatory for the innate immune compartment and beneficial for tumor control, while on the other hand, eATP can foster immune-suppressive mechanisms within the TME, thus contributing to tumor progression and metastasis. It is well established that T-cell immunity is pivotal in limiting tumor growth and possibly eradicating neoplastic cells. T cells are limited though in their antitumor activity through different mechanisms, such as exhaustion, anergy, and senescence; the pathways resulting in these cellular outcomes are not clear. Here, we review the function of P2X7 receptor in conditioning T cell-dependent immunity against cancer.

scholarly journals Orchestration of Adaptive T Cell Responses by Neutrophil Granule Contents

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Danielle Minns ◽  
Katie Jane Smith ◽  
Emily Gwyer Findlay
Keyword(s):  
Immune Response ◽  
Immune System ◽  
T Cell ◽  
Innate Immune System ◽  
Adaptive Immune Response ◽  
Innate Immune ◽  
T Cell Immunity ◽  
Cell Responses ◽  
Adaptive Immune ◽  
Cell Immunity

Neutrophils are the most abundant leukocytes in peripheral blood and respond rapidly to danger, infiltrating tissues within minutes of infectious or sterile injury. Neutrophils were long thought of as simple killers, but now we recognise them as responsive cells able to adapt to inflammation and orchestrate subsequent events with some sophistication. Here, we discuss how these rapid responders release mediators which influence later adaptive T cell immunity through influences on DC priming and directly on the T cells themselves. We consider how the release of granule contents by neutrophils—through NETosis or degranulation—is one way in which the innate immune system directs the phenotype of the adaptive immune response.

scholarly journals COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm

2020 ◽  
Vol 2020 ◽  
pp. 1-34
Author(s):  
Patrick C. Bradshaw ◽  
William A. Seeds ◽  
Alexandra C. Miller ◽  
Vikrant R. Mahajan ◽  
William M. Curtis
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
T Cell ◽  
Energy Metabolism ◽  
Respiratory Distress ◽  
Ketogenic Diet ◽  
Innate Immune Response ◽  
Redox State ◽  
Innate Immune ◽  
Cytokine Storm

Human SARS-CoV-2 infection is characterized by a high mortality rate due to some patients developing a large innate immune response associated with a cytokine storm and acute respiratory distress syndrome (ARDS). This is characterized at the molecular level by decreased energy metabolism, altered redox state, oxidative damage, and cell death. Therapies that increase levels of (R)-beta-hydroxybutyrate (R-BHB), such as the ketogenic diet or consuming exogenous ketones, should restore altered energy metabolism and redox state. R-BHB activates anti-inflammatory GPR109A signaling and inhibits the NLRP3 inflammasome and histone deacetylases, while a ketogenic diet has been shown to protect mice from influenza virus infection through a protective γδ T cell response and by increasing electron transport chain gene expression to restore energy metabolism. During a virus-induced cytokine storm, metabolic flexibility is compromised due to increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that damage, downregulate, or inactivate many enzymes of central metabolism including the pyruvate dehydrogenase complex (PDC). This leads to an energy and redox crisis that decreases B and T cell proliferation and results in increased cytokine production and cell death. It is hypothesized that a moderately high-fat diet together with exogenous ketone supplementation at the first signs of respiratory distress will increase mitochondrial metabolism by bypassing the block at PDC. R-BHB-mediated restoration of nucleotide coenzyme ratios and redox state should decrease ROS and RNS to blunt the innate immune response and the associated cytokine storm, allowing the proliferation of cells responsible for adaptive immunity. Limitations of the proposed therapy include the following: it is unknown if human immune and lung cell functions are enhanced by ketosis, the risk of ketoacidosis must be assessed prior to initiating treatment, and permissive dietary fat and carbohydrate levels for exogenous ketones to boost immune function are not yet established. The third limitation could be addressed by studies with influenza-infected mice. A clinical study is warranted where COVID-19 patients consume a permissive diet combined with ketone ester to raise blood ketone levels to 1 to 2 mM with measured outcomes of symptom severity, length of infection, and case fatality rate.

scholarly journals Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infection

2020 ◽  
Author(s):  
Jianmin Zuo ◽  
Alex Dowell ◽  
Hayden Pearce ◽  
Kriti Verma ◽  
Heather Long ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Antibody Level ◽  
Primary Infection ◽  
Natural Infection ◽  
T Cell Responses ◽  
Symptomatic Infection ◽  
Cell Responses ◽  
Cell Immunity

Abstract The immune response to SARS-CoV-2 is critical in both controlling primary infection and preventing re-infection. However, there is concern that immune responses following natural infection may not be sustained and that this may predispose to recurrent infection. We analysed the magnitude and phenotype of the SARS-CoV-2 cellular immune response in 100 donors at six months following primary infection and related this to the profile of antibody level against spike, nucleoprotein and RBD over the previous six months. T-cell immune responses to SARS-CoV-2 were present by ELISPOT or ICS analysis in all donors and are characterised by predominant CD4+ T cell responses with strong IL-2 cytokine expression. Median T-cell responses were 50% higher in donors who had experienced an initial symptomatic infection indicating that the severity of primary infection establishes a ‘setpoint’ for cellular immunity that lasts for at least 6 months. The T-cell responses to both spike and nucleoprotein/membrane proteins were strongly correlated with the peak antibody level against each protein. The rate of decline in antibody level varied between individuals and higher levels of nucleoprotein-specific T cells were associated with preservation of NP-specific antibody level although no such correlation was observed in relation to spike-specific responses. In conclusion, our data are reassuring that functional SARS-CoV-2-specific T-cell responses are retained at six months following infection although the magnitude of this response is related to the clinical features of primary infection.

scholarly journals Longitudinal single-cell immune profiling revealed distinct innate immune response in asymptomatic COVID-19 patients

2020 ◽  
Author(s):  
Xiang-Na Zhao ◽  
Yue You ◽  
Guo-Lin Wang ◽  
Hui-Xia Gao ◽  
Xiao-Ming Cui ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Innate Immune Response ◽  
Clonal Expansion ◽  
Innate Immune ◽  
Type I ◽  
Severe Condition ◽  
Asymptomatic Patients

SUMMARYRecent studies have characterized the single-cell immune landscape of host immune response of coronavirus disease 2019 (COVID-19), specifically focus on the severe condition. However, the immune response in mild or even asymptomatic patients remains unclear. Here, we performed longitudinal single-cell transcriptome sequencing and T cell/B cell receptor sequencing on 3 healthy donors and 10 COVID-19 patients with asymptomatic, moderate, and severe conditions. We found asymptomatic patients displayed distinct innate immune responses, including increased CD56briCD16− NK subset, which was nearly missing in severe condition and enrichment of a new Th2-like cell type/state expressing a ciliated cell marker. Unlike that in moderate condition, asymptomatic patients lacked clonal expansion of effector CD8+ T cells but had a robust effector CD4+ T cell clonal expansion, coincide with previously detected SARS-CoV-2-reactive CD4+ T cells in unexposed individuals. Moreover, NK and effector T cells in asymptomatic patients have upregulated cytokine related genes, such as IFNG and XCL2. Our data suggest early innate immune response and type I immunity may contribute to the asymptomatic phenotype in COVID-19 disease, which could in turn deepen our understanding of severe COVID-19 and guide early prediction and therapeutics.

scholarly journals TCR Repertoire Characterization for T Cells Expanded in Response to hRSV Infection in Mice Immunized with a Recombinant BCG Vaccine

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 233
Author(s):  
Emma Rey-Jurado ◽  
Karen Bohmwald ◽  
Hernán G. Correa ◽  
Alexis M. Kalergis
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Response ◽  
Bcg Vaccine ◽  
Lung Damage ◽  
Cell Repertoire ◽  
Cell Immunity ◽  
Tcr Repertoire ◽  
Syncytial Virus

T cells play an essential role in the immune response against the human respiratory syncytial virus (hRSV). It has been described that both CD4+ and CD8+ T cells can contribute to the clearance of the virus during an infection. However, for some individuals, such an immune response can lead to an exacerbated and detrimental inflammatory response with high recruitment of neutrophils to the lungs. The receptor of most T cells is a heterodimer consisting of α and β chains (αβTCR) that upon antigen engagement induces the activation of these cells. The αβTCR molecule displays a broad sequence diversity that defines the T cell repertoire of an individual. In our laboratory, a recombinant Bacille Calmette–Guérin (BCG) vaccine expressing the nucleoprotein (N) of hRSV (rBCG-N-hRSV) was developed. Such a vaccine induces T cells with a Th1 polarized phenotype that promote the clearance of hRSV infection without causing inflammatory lung damage. Importantly, as part of this work, the T cell receptor (TCR) repertoire of T cells expanded after hRSV infection in naïve and rBCG-N-hRSV-immunized mice was characterized. A more diverse TCR repertoire was observed in the lungs from rBCG-N-hRSV-immunized as compared to unimmunized hRSV-infected mice, suggesting that vaccination with the recombinant rBCG-N-hRSV vaccine triggers the expansion of T cell populations that recognize more viral epitopes. Furthermore, differential expansion of certain TCRVβ chains was found for hRSV infection (TCRVβ+8.3 and TCRVβ+5.1,5.2) as compared to rBCG-N-hRSV vaccination (TCRVβ+11 and TCRVβ+12). Our findings contribute to better understanding the T cell response during hRSV infection, as well as the functioning of a vaccine that induces a protective T cell immunity against this virus.

scholarly journals P02.03 Microwave ablation enhances tumor-specific immune response in patients with hepatocellular carcinoma

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A21.1-A21
Author(s):  
E Staib ◽  
K Leuchte ◽  
M Thelen ◽  
P Gödel ◽  
A Lechner ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Thermal Ablation ◽  
Microwave Ablation ◽  
T Cell Response ◽  
Tumor Control ◽  
Free Survival ◽  
Interleukin 5 ◽  
The Impact

BackgroundThermal ablative therapies, such as microwave ablation (MWA) or radiofrequency ablation (RFA), are standard treatments for HCC. In addition to the local tumor destruction, abscopal effects (a reduction of a tumor mass in areas that were not included in the thermal ablation) could be observed. These systemic effects may be mediated by anti-tumor immune response, which has been described for RFA. MWA is rapidly replacing RFA, but systemic immunostimulatory effects of MWA treatment have been poorly studied.Materials and MethodsPatients receiving MWA for localized HCC were included in this study. Effects of MWA on peripheral blood mononuclear cells (PBMC) of HCC patients treated with MWA were analyzed by multicolor flow cytometry. Tumor-specific immune responses against 7 shared tumor antigens were analyzed using peptide pools in 3-color Fluorospot assays (Interferon-y/Interleukin-5/Interleukin-10). The impact of type, density and localization of tumor-infiltrating lymphocytes was assessed by immunohistochemistry (IHC) of CD3, CD4, CD8, FoxP3, CD38 and CD20 and digital image analyses (Immunoscore) of tumor specimens in an additional cohort of patients who received combined surgical resection and thermal ablation.ResultsWhile comprehensive flow cytometric analyses in sequential samples (day 0, 7 and 90) of a prospective patient cohort (n=23) demonstrated only moderate effects of MWA on circulating immune cell subsets, Fluorospot analyses revealed de novo or enhanced tumor-specific immune responses in 30% of these patients. This anti-tumor immune response was related to tumor control. Interferon-y and Interleukin-5 T cell responses against cancer testis antigens were more frequent in patients with a long-time remission (>12 months) after MWA (7/16) compared to patients suffering from an early relapse (0/13 patients). Presence of tumor-specific T cell response (Interferon-y and/or Interleukin-5) was associated to longer progression-free survival (15.0 vs. 10.0 months). Immunohistochemical analyses of resected tumor samples revealed that a high T cell infiltration in a second tumor lesion at the time of thermal ablation was associated with superior disease-free survival (37.4 vs. 13.1 months).ConclusionsOur data demonstrates remarkable immune-related effects of MWA in HCC patients. This study and provides additional evidence for a combination of thermal ablation and immunotherapy in this challenging disease.Funding‘Koeln Fortune’ and ‘CAP-CMMC’ local research grant (to P.G. and H.A.S.) supported our research.Disclosure InformationE. Staib: None. K. Leuchte: None. M. Thelen: None. P. Gödel: None. A. Lechner: None. P. Zentis: None. M. Garcia-Marquez: None. D. Waldschmidt: None. R.R. Datta: None. R. Wahba: None. C. Wybranski: None. T. Zander: None. A. Quaas: None. U. Drebber: None. D.L. Stippel: None. C. Bruns: None. K. Wennhold: None. M. von Bergwelt-Baildon: None. H.A. Schlösser: None.

scholarly journals Phenoloxidase activity and haemolymph cytology in honeybees challenged with a virus suspension (deformed wings virus DWV) or phosphate buffered suspension (PBS)

2019 ◽  
Vol 49 (2) ◽  
Author(s):  
Francesca Millanta ◽  
Simona Sagona ◽  
Maurizio Mazzei ◽  
Mario Forzan ◽  
Alessandro Poli ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Immune Responses ◽  
Innate Immune System ◽  
Innate Immune ◽  
Additional Stress ◽  
Varroa Mite ◽  
Virus Suspension ◽  
Phenoloxidase Activity ◽  
Cell Immunity

ABSTRACT: The innate immune system of honeybees mainly consists in antimicrobial peptides, cellular immunity and melanisation. In order to investigate the immune response of honeybees to immune stressors, three stress degrees were tested. Newly emerged bees naturally DWV-infected were collected from a Varroa mite-free apiary and divided into three experimental groups: naturally DWV infected bees, PBS injected bees, and artificially DWV super infected bees. Phenoloxidase activity and haemolymph cellular subtype count were investigated. Phenoloxidase activity was highest (P<0.05) in DWV-superinfected bees, and the haemocyte population differed within the three observed groups. Although, immune responses following DWV infection have still not been completely clarified, this investigation sheds light on the relation between cell immunity and the phenoloxidase activity of DWV-naturally infected honeybees exposed to additional stress such as injury and viral superinfection.

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