An Interactive Classroom Icebreaker and Parting-Ways Activity to Introduce and Review the Effector Functions of Cellular Players Associated with the Immune Response
               
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The first vaccines ever made were based on live-attenuated or inactivated pathogens, either whole cells or fragments. Although these vaccines required the co-administration of antigens with adjuvants to induce a strong humoral response, they could only elicit a poor CD8+ T-cell response. In contrast, next-generation nano/microparticle-based vaccines offer several advantages over traditional ones because they can induce a more potent CD8+ T-cell response and, at the same time, are ideal carriers for proteins, adjuvants, and nucleic acids. The fact that these nanocarriers can be loaded with molecules able to modulate the immune response by inducing different effector functions and regulatory activities makes them ideal tools for inverse vaccination, whose goal is to shut down the immune response in autoimmune diseases. Poly (lactic-co-glycolic acid) (PLGA) and liposomes are biocompatible materials approved by the Food and Drug Administration (FDA) for clinical use and are, therefore, suitable for nanoparticle-based vaccines. Recently, another candidate platform for innovative vaccines based on extracellular vesicles (EVs) has been shown to efficiently co-deliver antigens and adjuvants. This review will discuss the potential use of PLGA-NPs, liposomes, and EVs as carriers of peptides, adjuvants, mRNA, and DNA for the development of next-generation vaccines against endemic and emerging viruses in light of the recent COVID-19 pandemic.

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Harnessing NK Cell Checkpoint-Modulating Immunotherapies

Cancers ◽

10.3390/cancers12071807 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1807 ◽

Cited By ~ 1

Author(s):

Sachin Kumar Singh Chauhan ◽

Ulrike Koehl ◽

Stephan Kloess

Keyword(s):

Immune Response ◽

Immune Checkpoint ◽

Nk Cell ◽

Checkpoint Inhibitors ◽

Therapeutic Interventions ◽

Immune Checkpoints ◽

Effector Functions ◽

Self Tolerance ◽

Underlying Mechanisms

During the host immune response, the precise balance of the immune system, regulated by immune checkpoint, is required to avoid infection and cancer. These immune checkpoints are the mainstream regulator of the immune response and are crucial for self-tolerance. During the last decade, various new immune checkpoint molecules have been studied, providing an attractive path to evaluate their potential role as targets for effective therapeutic interventions. Checkpoint inhibitors have mainly been explored in T cells until now, but natural killer (NK) cells are a newly emerging target for the determination of checkpoint molecules. Simultaneously, an increasing number of therapeutic dimensions have been explored, including modulatory and inhibitory checkpoint molecules, either causing dysfunction or promoting effector functions. Furthermore, the combination of the immune checkpoint with other NK cell-based therapeutic strategies could also strengthen its efficacy as an antitumor therapy. In this review, we have undertaken a comprehensive review of the literature to date regarding underlying mechanisms of modulatory and inhibitory checkpoint molecules.

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Interleukin-32 in Infection, Inflammation and Cancer Biology

Serbian Journal of Experimental and Clinical Research ◽

10.1515/sjecr-2016-0085 ◽

2020 ◽

Vol 21 (1) ◽

pp. 75-82

Author(s):

Mladen Pavlovic ◽

Ivan Jovanovic ◽

Nebojsa Arsenijevic

Keyword(s):

Immune Response ◽

Immune System ◽

Immune Cells ◽

Proinflammatory Cytokine ◽

Cancer Biology ◽

Clonal Expansion ◽

Acquired Immunity ◽

Effector Functions

AbstractCytokines are small pleiotropic polypeptids secreted dominantly by the cells of the immune system. These polypeptids are main mediators of innate and acquired immunity, responsible for clonal expansion and differentiation of immune cells, initiation of immune response and enhancing of effector functions of leukocytes. Cytokine-related effects are most studied in the fields of inflammation, immunology, and cancer biology. In this review we discuss one of the most intriguing, recently discovered proinflammatory cytokine, interleukin 32.

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TREM-1 ligand expression on platelets enhances neutrophil activation

Blood ◽

10.1182/blood-2007-01-069195 ◽

2007 ◽

Vol 110 (3) ◽

pp. 1029-1035 ◽

Cited By ~ 120

Author(s):

Philipp Haselmayer ◽

Ludger Grosse-Hovest ◽

Philipp von Landenberg ◽

Hansjörg Schild ◽

Markus P. Radsak

Keyword(s):

Immune Response ◽

Specific Binding ◽

Human Platelets ◽

Innate Immune ◽

Rodent Models ◽

Ligand Interaction ◽

Effector Functions ◽

Ligand Expression ◽

Severe Infections ◽

Future Concepts

Abstract The triggering receptor expressed on myeloid cells 1 (TREM-1) plays an important role in the innate immune response related to severe infections and sepsis. Modulation of TREM-1–associated activation improves the outcome in rodent models for pneumonia and sepsis. However, the identity and occurrence of the natural TREM-1 ligands are so far unknown, impairing the further understanding of the biology of this receptor. Here, we report the presence of a ligand for TREM-1 on human platelets. Using a recombinant TREM-1 fusion protein, we demonstrate specific binding of TREM-1 to platelets. TREM-1–specific signals are required for the platelet-induced augmentation of polymorphonuclear leukocyte (PMN) effector functions (provoked by LPS). However, TREM-1 interaction with its ligand is not required for platelet/PMN complex formation, which is dependent on integrins and selectins. Taken together, the results indicate that the TREM-1 ligand is expressed by platelets, and the TREM-1/ligand interaction contributes to the amplification of LPS-induced PMN activation. Our results shed new light on our understanding of TREM-1 and its role in the innate inflammatory response in infections and might contribute to the development of future concepts to treat sepsis.

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The Role of the Cytoskeleton in Regulating the Natural Killer Cell Immune Response in Health and Disease: From Signaling Dynamics to Function

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.609532 ◽

2021 ◽

Vol 9 ◽

Author(s):

Aviad Ben-Shmuel ◽

Batel Sabag ◽

Guy Biber ◽

Mira Barda-Saad

Keyword(s):

Immune Response ◽

Nk Cells ◽

Signaling Pathways ◽

Natural Killer ◽

Immunological Synapse ◽

Nk Cell ◽

Cell Immune Response ◽

Effector Functions ◽

Health And Disease

Natural killer (NK) cells are innate lymphoid cells, which play key roles in elimination of virally infected and malignant cells. The balance between activating and inhibitory signals derived from NK surface receptors govern the NK cell immune response. The cytoskeleton facilitates most NK cell effector functions, such as motility, infiltration, conjugation with target cells, immunological synapse assembly, and cytotoxicity. Though many studies have characterized signaling pathways that promote actin reorganization in immune cells, it is not completely clear how particular cytoskeletal architectures at the immunological synapse promote effector functions, and how cytoskeletal dynamics impact downstream signaling pathways and activation. Moreover, pioneering studies employing advanced imaging techniques have only begun to uncover the architectural complexity dictating the NK cell activation threshold; it is becoming clear that a distinct organization of the cytoskeleton and signaling receptors at the NK immunological synapse plays a decisive role in activation and tolerance. Here, we review the roles of the actin cytoskeleton in NK cells. We focus on how actin dynamics impact cytolytic granule secretion, NK cell motility, and NK cell infiltration through tissues into inflammatory sites. We will also describe the additional cytoskeletal components, non-muscle Myosin II and microtubules that play pivotal roles in NK cell activity. Furthermore, special emphasis will be placed on the role of the cytoskeleton in assembly of immunological synapses, and how mutations or downregulation of cytoskeletal accessory proteins impact NK cell function in health and disease.

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Collaboration between the Fab and Fc contribute to maximal protection against SARS-CoV-2 following NVX-CoV2373 subunit vaccine with Matrix-M™ vaccination

10.21203/rs.3.rs-200342/v1 ◽

2021 ◽

Cited By ~ 1

Author(s):

Galit Alter ◽

Matthew Gorman ◽

Nita Patel ◽

Mimi Guebre-Xabier ◽

Alex Zhu ◽

...

Keyword(s):

Immune Response ◽

Single Dose ◽

Respiratory Tract ◽

Protective Immunity ◽

Lower Respiratory Tract ◽

Subunit Vaccine ◽

Antigen Dose ◽

Effector Functions ◽

Humoral Immune ◽

Dose Levels

Abstract Recently approved vaccines have already shown remarkable protection in limiting SARS-CoV-2 associated disease. However, immunologic mechanism(s) of protection, as well as how boosting alters immunity to wildtype and newly emerging strains, remain incompletely understood. Here we deeply profiled the humoral immune response in a cohort of non-human primates immunized with a stable recombinant full-length SARS-CoV-2 spike (S) glycoprotein (NVX-CoV2373) at two dose levels, administered as a single or two-dose regimen with a saponin-based adjuvant Matrix-M™. While antigen dose had some effect on Fc-effector profiles, both antigen dose and boosting significantly altered overall titers, neutralization and Fc-effector profiles, driving unique vaccine-induced antibody fingerprints. Combined differences in antibody effector functions and neutralization were strongly associated with distinct levels of protection in the upper and lower respiratory tract, pointing to the presence of combined, but distinct, compartment-specific neutralization and Fc-mechanisms as key determinants of protective immunity against infection. Moreover, NVX-CoV2373 elicited antibodies functionally target emerging SARS-CoV-2 variants, collectively pointing to the critical collaborative role for Fab and Fc in driving maximal protection against SARS-CoV-2. Collectively, the data presented here suggest that a single dose may prevent disease, but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants.

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Targeting nucleotide metabolism as the nexus of viral infections, cancer, and the immune response

Science Advances ◽

10.1126/sciadv.abg6165 ◽

2021 ◽

Vol 7 (21) ◽

pp. eabg6165

Author(s):

Yarden Ariav ◽

James H Ch’ng ◽

Heather R. Christofk ◽

Noga Ron-Harel ◽

Ayelet Erez

Keyword(s):

Immune Response ◽

Immune System ◽

Viral Infections ◽

Nucleotide Metabolism ◽

Treatment Modalities ◽

Host Immune System ◽

Nucleotide Synthesis ◽

Effector Functions ◽

Signaling Mechanisms ◽

Infected Cells

Virus-infected cells and cancers share metabolic commonalities that stem from their insatiable need to replicate while evading the host immune system. These similarities include hijacking signaling mechanisms that induce metabolic rewiring in the host to up-regulate nucleotide metabolism and, in parallel, suppress the immune response. In both cancer and viral infections, the host immune cells and, specifically, lymphocytes augment nucleotide synthesis to support their own proliferation and effector functions. Consequently, established treatment modalities targeting nucleotide metabolism against cancers and virally infected cells may result in restricted immune response. Encouragingly, following the introduction of immunotherapy against cancers, multiple studies improved our understanding for improving antigen presentation to the immune system. We propose here that understanding the immune consequences of targeting nucleotide metabolism against cancers may be harnessed to optimize therapy against viral infections.

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Long-Lasting Protective Antiviral Immunity Induced by Passive Immunotherapies Requires both Neutralizing and Effector Functions of the Administered Monoclonal Antibody

Journal of Virology ◽

10.1128/jvi.00568-10 ◽

2010 ◽

Vol 84 (19) ◽

pp. 10169-10181 ◽

Cited By ~ 21

Author(s):

Roudaina Nasser ◽

Mireia Pelegrin ◽

Henri-Alexandre Michaud ◽

Marc Plays ◽

Marc Piechaczyk ◽

...

Keyword(s):

Monoclonal Antibody ◽

Immune Response ◽

Viral Infections ◽

Short Treatment ◽

Newborn Mice ◽

Antiviral Immune Response ◽

Viral Propagation ◽

Effector Functions ◽

Endogenous Immune Response ◽

Immunomodulatory Action

ABSTRACT Using FrCasE retrovirus-infected newborn mice as a model system, we have shown recently that a long-lasting antiviral immune response essential for healthy survival emerges after a short treatment with a neutralizing (667) IgG2a isotype monoclonal antibody (MAb). This suggested that the mobilization of adaptive immunity by administered MAbs is key for the success in the long term for the MAb-based passive immunotherapy of chronic viral infections. We have addressed here whether the anti-FrCasE protective endogenous immunity is the mere consequence of viral propagation blunting, which would simply give time to the immune system to react, and/or to actual immunomodulation by the MAb during the treatment. To this aim, we have compared viral replication, disease progression, and antiviral immune responses between different groups of infected mice: (i) mice treated with either the 667 MAb, its F(ab′)2 fragment, or an IgM (672) with epitopic specificity similar to that of 667 but displaying different effector functions, and (ii) mice receiving no treatment but infected with a low viral inoculum reproducing the initial viral expansion observed in their infected/667 MAb-treated counterparts. Our data show that the reduction of FrCasE propagation is insufficient on its own to induce protective immunity and support a direct immunomodulatory action of the 667 MAb. Interestingly, they also point to sequential actions of the administered MAb. In a first step, viral propagation is exclusively controlled by 667 neutralizing activity, and in a second one, this action is complemented by FcγR-binding-dependent mechanisms, which most likely combine infected cell cytolysis and the modulation of the antiviral endogenous immune response. Such complementary effects of administered MAbs must be taken into consideration for the improvement of future antiviral MAb-based immunotherapies.

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The role of γδТ- and NK-сells in immune response

Bulletin of Siberian Medicine ◽

10.20538/1682-0363-2010-5-138-142 ◽

2010 ◽

Vol 9 (5) ◽

pp. 138-142 ◽

Cited By ~ 1

Author(s):

Ye. G. Churina ◽

O. I. Urazova ◽

V. V. Novitsky ◽

I. O. Naslednikova ◽

O. V. Voronkova

Keyword(s):

Immune Response ◽

Nk Cells ◽

Inhibitory Effect ◽

Antibacterial Action ◽

Effector Functions

The article presents up-to-date literature data on the role of γδТ-cells and different NK-cells subpopulations in the immune response. Their origin, immunophenotypes, range of secreted cytokines as well as effector functions and factors having stimulating and inhibitory effect on γδТ- and NK-cells are described. Mechanisms of antibacterial action of this type of cells are analyzed.

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The Role of Metabolic Enzymes in the Regulation of Inflammation

Metabolites ◽

10.3390/metabo10110426 ◽

2020 ◽

Vol 10 (11) ◽

pp. 426

Author(s):

Wesley H. Godfrey ◽

Michael D. Kornberg

Keyword(s):

Immune Response ◽

Metabolic Networks ◽

Clinical Intervention ◽

Metabolic Enzymes ◽

Metabolic Reprogramming ◽

Effector Functions ◽

Downstream Effector ◽

Moonlighting Functions ◽

External Stimuli

Immune cells undergo dramatic metabolic reprogramming in response to external stimuli. These metabolic pathways, long considered as simple housekeeping functions, are increasingly understood to critically regulate the immune response, determining the activation, differentiation, and downstream effector functions of both lymphoid and myeloid cells. Within the complex metabolic networks associated with immune activation, several enzymes play key roles in regulating inflammation and represent potential therapeutic targets in human disease. In some cases, these enzymes control flux through pathways required to meet specific energetic or metabolic demands of the immune response. In other cases, key enzymes control the concentrations of immunoactive metabolites with direct roles in signaling. Finally, and perhaps most interestingly, several metabolic enzymes have evolved moonlighting functions, with roles in the immune response that are entirely independent of their conventional enzyme activities. Here, we review key metabolic enzymes that critically regulate inflammation, highlighting mechanistic insights and opportunities for clinical intervention.

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