Hepatic NKT cells: friend or foe?

2008 ◽  
Vol 114 (7) ◽  
pp. 457-466 ◽  
Author(s):  
Mark G. Swain
Keyword(s):  
Immune Response ◽  
Fas Ligand ◽  
Cell Types ◽  
Cd40 Ligand ◽  
Nkt Cells ◽  
Innate Immune ◽  
Nkt Cell ◽  
Cell Surface Molecule ◽  
Infected Cells ◽  
Parenchymal Cells

The innate immune system represents a critical first line of host response to infectious, injurious and inflammatory insults. NKT cells (natural killer T-cells) are an important, but relatively poorly understood, component of the innate immune response. Moreover, NKT cells are enriched within the liver, suggesting that within the hepatic compartment NKT cells probably fulfil important roles in the modulation of the immune response to infection or injury. NKT cells are characterized by their rapid activation and secretion of large amounts of numerous types of cytokines, including those within the Th1-type, Th2-type and Th17-type groups, which in turn can interact with a multitude of other cell types within the liver. In addition, NKT cells are capable of participating in a wide array of effector functions with regards to other cell types via NKT cell-surface-molecule expression [e.g. FASL (FAS ligand) and CD40L (CD40 ligand)] and the release of mediators (e.g. perforin and granzyme) contained in cellular granules, which in turn can activate or destroy other cells (i.e. immune or parenchymal cells) within the liver. Given the huge scope of potential actions that can be mediated by NKT cells, it has become increasingly apparent that NKT cells may fulfil both beneficial (e.g. clearance of virally infected cells) and harmful (e.g. induction of autoimmunity) roles in the setting of liver disease. This review will outline the possible roles which may be played by NKT cells in the setting of specific liver diseases or conditions, and will discuss the NKT cell in the context of its role as either a ‘friend’ or a ‘foe’ with respect to the outcome of these liver disorders.

CF Monocyte Derived Macrophages Have an Attenuated Response to Extracellular Vesicles Secreted by Airway Epithelial Cells

2021 ◽  
Author(s):  
Katja Koeppen ◽  
Amanda B Nymon ◽  
Roxanna Barnaby ◽  
Zhongyou Li ◽  
Thomas H Hampton ◽  
...  
Keyword(s):  
Immune Response ◽  
Epithelial Cells ◽  
Bacterial Infection ◽  
Extracellular Vesicles ◽  
Cell Types ◽  
Airway Epithelial Cells ◽  
Innate Immune ◽  
Airway Epithelial ◽  
Immune Genes ◽  
Innate Immune Genes

Mutations in CFTR alter macrophage responses, for example, by reducing their ability to phagocytose and kill bacteria. Altered macrophage responses may facilitate bacterial infection and inflammation in the lungs, contributing to morbidity and mortality in cystic fibrosis (CF). Extracellular vesicles (EVs) are secreted by multiple cell types in the lungs and participate in the host immune response to bacterial infection, but the effect of EVs secreted by CF airway epithelial cells (AEC) on CF macrophages is unknown. This report examines the effect of EVs secreted by primary AEC on monocyte derived macrophages (MDM) and contrasts responses of CF and WT MDM. We found that EVs generally increase pro-inflammatory cytokine secretion and expression of innate immune genes in MDM, especially when EVs are derived from AEC exposed to Pseudomonas aeruginosa, and that this effect is attenuated in CF MDM. Specifically, EVs secreted by P. aeruginosa exposed AEC induced immune response genes and increased secretion of pro-inflammatory cytokines, chemoattractants and chemokines involved in tissue repair by WT MDM, but these effects were less robust in CF MDM. We attribute attenuated responses by CF MDM to differences between CF and WT macrophages because EVs secreted by CF AEC or WT AEC elicited similar responses in CF MDM. Our findings demonstrate the importance of AEC EVs in macrophage responses and show that the Phe508del mutation in CFTR attenuates the innate immune response of MDM to EVs.

scholarly journals Mutations in a Highly Conserved Motif of nsp1β Protein Attenuate the Innate Immune Suppression Function of Porcine Reproductive and Respiratory Syndrome Virus

2016 ◽  
Vol 90 (7) ◽  
pp. 3584-3599 ◽  
Author(s):  
Yanhua Li ◽  
Duan-Liang Shyu ◽  
Pengcheng Shang ◽  
Jianfa Bai ◽  
Kang Ouyang ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Innate Immune ◽  
Respiratory Syndrome Virus ◽  
Adaptive Immune Responses ◽  
Virus Growth ◽  
Conserved Motif ◽  
Adaptive Immune ◽  
Infected Cells ◽  
Growth Ability

ABSTRACTPorcine reproductive and respiratory syndrome virus (PRRSV) nonstructural protein 1β (nsp1β) is a multifunctional viral protein, which is involved in suppressing the host innate immune response and activating a unique −2/−1 programmed ribosomal frameshifting (PRF) signal for the expression of frameshifting products. In this study, site-directed mutagenesis analysis showed that the R128A or R129A mutation introduced into a highly conserved motif (123GKYLQRRLQ131) reduced the ability of nsp1β to suppress interferon beta (IFN-β) activation and also impaired nsp1β's function as a PRF transactivator. Three recombinant viruses, vR128A, vR129A, and vRR129AA, carrying single or double mutations in the GKYLQRRLQ motif were characterized. In comparison to the wild-type (WT) virus, vR128A and vR129A showed slightly reduced growth abilities, while the vRR129AA mutant had a significantly reduced growth ability in infected cells. Consistent with the attenuated growth phenotypein vitro, pigs infected with nsp1β mutants had lower levels of viremia than did WT virus-infected pigs. Compared to the WT virus in infected cells, all three mutated viruses stimulated high levels of IFN-α expression and exhibited a reduced ability to suppress the mRNA expression of selected interferon-stimulated genes (ISGs). In pigs infected with nsp1β mutants, IFN-α production was increased in the lungs at early time points postinfection, which was correlated with increased innate NK cell function. Furthermore, the augmented innate response was consistent with the increased production of IFN-γ in pigs infected with mutated viruses. These data demonstrate that residues R128 and R129 are critical for nsp1β function and that modifying these key residues in the GKYLQRRLQ motif attenuates virus growth ability and improves the innate and adaptive immune responses in infected animals.IMPORTANCEPRRSV infection induces poor antiviral innate IFN and cytokine responses, which results in weak adaptive immunity. One of the strategies in next-generation vaccine construction is to manipulate viral proteins/genetic elements involved in antagonizing the host immune response. PRRSV nsp1β was identified to be a strong innate immune antagonist. In this study, two basic amino acids, R128 and R129, in a highly conserved GKYLQRRLQ motif were determined to be critical for nsp1β function. Mutations introduced into these two residues attenuated virus growth and improved the innate and adaptive immune responses of infected animals. Technologies developed in this study could be broadly applied to current commercial PRRSV modified live-virus (MLV) vaccines and other candidate vaccines.

scholarly journals The Natural Killer T (NKT) Cell Ligand α-Galactosylceramide Demonstrates Its Immunopotentiating Effect by Inducing Interleukin (IL)-12 Production by Dendritic Cells and IL-12 Receptor Expression on NKT Cells

1999 ◽  
Vol 189 (7) ◽  
pp. 1121-1128 ◽  
Author(s):  
Hidemitsu Kitamura ◽  
Kenji Iwakabe ◽  
Takashi Yahata ◽  
Shin-ichiro Nishimura ◽  
Akio Ohta ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Natural Killer ◽  
Cd40 Ligand ◽  
Nkt Cells ◽  
Receptor Expression ◽  
Antitumor Activities ◽  
Nkt Cell ◽  
Ifn Γ ◽  
Natural Killer T

The natural killer T (NKT) cell ligand α-galactosylceramide (α-GalCer) exhibits profound antitumor activities in vivo that resemble interleukin (IL)-12–mediated antitumor activities. Because of these similarities between the activities of α-GalCer and IL-12, we investigated the involvement of IL-12 in the activation of NKT cells by α-GalCer. We first established, using purified subsets of various lymphocyte populations, that α-GalCer selectively activates NKT cells for production of interferon (IFN)-γ. Production of IFN-γ by NKT cells in response to α-GalCer required IL-12 produced by dendritic cells (DCs) and direct contact between NKT cells and DCs through CD40/CD40 ligand interactions. Moreover, α-GalCer strongly induced the expression of IL-12 receptor on NKT cells from wild-type but not CD1−/− or Vα14−/− mice. This effect of α-GalCer required the production of IFN-γ by NKT cells and production of IL-12 by DCs. Finally, we showed that treatment of mice with suboptimal doses of α-GalCer together with suboptimal doses of IL-12 resulted in strongly enhanced natural killing activity and IFN-γ production. Collectively, these findings indicate an important role for DC-produced IL-12 in the activation of NKT cells by α-GalCer and suggest that NKT cells may be able to condition DCs for subsequent immune responses. Our results also suggest a novel approach for immunotherapy of cancer.

scholarly journals Augmentation of Vα14 Nkt Cell–Mediated Cytotoxicity by Interleukin 4 in an Autocrine Mechanism Resulting in the Development of Concanavalin a–Induced Hepatitis

2000 ◽  
Vol 191 (1) ◽  
pp. 105-114 ◽  
Author(s):  
Yoshikatsu Kaneko ◽  
Michishige Harada ◽  
Tetsu Kawano ◽  
Masakatsu Yamashita ◽  
Youichi Shibata ◽  
...  
Keyword(s):  
Concanavalin A ◽  
Molecular Mechanisms ◽  
Fas Ligand ◽  
Granzyme B ◽  
Nkt Cells ◽  
Interleukin 4 ◽  
Con A ◽  
Short Term Treatment ◽  
Nkt Cell ◽  
Hepatocyte Injury

The administration of concanavalin A (Con A) induces a rapid severe injury of hepatocytes in mice. Although the Con A–induced hepatitis is considered to be an experimental model of human autoimmune hepatitis, the precise cellular and molecular mechanisms that induce hepatocyte injury remain unclear. Here, we demonstrate that Vα14 NKT cells are required and sufficient for induction of this hepatitis. Moreover, interleukin (IL)-4 produced by Con A–activated Vα14 NKT cells is found to play a crucial role in disease development by augmenting the cytotoxic activity of Vα14 NKT cells in an autocrine fashion. Indeed, short-term treatment with IL-4 induces an increase in the expression of granzyme B and Fas ligand (L) in Vα14 NKT cells. Moreover, Vα14 NKT cells from either perforin knock-out mice or FasL-mutant gld/gld mice fail to induce hepatitis, and hence perforin–granzyme B and FasL appear to be effector molecules in Con A–induced Vα14 NKT cell–mediated hepatocyte injury.

scholarly journals The Nonstructural Proteins 3 and 5 from Flavivirus Modulate Nuclear-Cytoplasmic Transport and Innate Immune Response Targeting Nuclear Proteins

2018 ◽  
Author(s):  
Margot Cervantes-Salazar ◽  
Ana L. Gutiérrez-Escolano ◽  
José M. Reyes-Ruiz ◽  
Rosa M. del Angel
Keyword(s):  
Immune Response ◽  
Nuclear Pore Complex ◽  
Innate Immune ◽  
Nuclear Proteins ◽  
Nuclear Pore ◽  
Cytoplasmic Transport ◽  
Infected Cells ◽  
Main Regulator ◽  
Mature Mrnas ◽  
Replicative Cycle

ABSTRACTViruses hijack cellular proteins and components to be replicated in the host cell and to evade the immune response. Although flaviviruses have a cytoplasmic replicative cycle, some viral proteins such as the capsid (C) and the RNA dependent RNA polymerase, NS5, can reach the nucleus of the infected cells. Considering the important roles of NS5 in viral replication and in the control of the immune response, and its striking presence in the nucleus, the possible functions of this protein in some mechanisms orchestrated by the nucleus was analyzed. We isolated and identified nuclear proteins that interact with NS5; one of them, the DEAD-box RNA helicase DDX5 is relocated to the cytoplasm and degraded during infection with DENV, which correlates with its function in IFN dependent response. Since DDX5 and many other proteins are relocated from the nucleus to the cytoplasm during flavivirus infection, the integrity and function of the main regulator of the nuclear-cytoplasmic transport, the nuclear pore complex (NPC) was evaluated. We found that during DENV and ZIKV infection nucleoporins (NUPs) such as TPR, Nup153, Nup98, and Nup62 were cleavaged/degraded. The protease NS2B-NS3 induces NUPs degradation and it causes a dramatic inhibition of mature mRNAs export to the cytoplasm but not the export of DDX5 protein, which is dependent on NS5. Here we describe for the first time that the NS3 and NS5 proteins from flavivirus play novel functions hijacking the NPC and some nuclear proteins relevant in triggering immune response pathways, inducing a favorable environment for viral replication.IMPORTANCEViruses, as intracellular obligate parasites, hijack cellular components to enter and replicate in infected cells. Remarkably, in many cases, viruses hijack molecules with crucial functions for the cells. Here it is described how RNA viruses such as DENV and ZIKV, with a cytoplasmic replicative cycle, use NS3 and NS5, two of their unique non-structural proteins with enzymatic activity, to modulate nuclear-cytoplasmic transport. We found that NS3 disrupts the nuclear pore complex, the main regulator in nuclear-cytoplasmic transport, causing a strong reduction in the amount of mature mRNAs in the cytoplasm and an inhibition in innate immune response. Additionally, NS5 induces the relocation of nuclear proteins to the cytoplasm such as DDX5, involved in immune response, which is later degraded by NS3. These findings allow the understanding of crucial mechanisms that viruses use to deal with the control of the immune response to grant the production of new viral particles.

scholarly journals Recent Advances on the Innate Immune Response to Coxiella burnetii

2021 ◽  
Vol 11 ◽  
Author(s):  
Guido Sireci ◽  
Giusto Davide Badami ◽  
Diana Di Liberto ◽  
Valeria Blanda ◽  
Francesca Grippi ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Coxiella Burnetii ◽  
Q Fever ◽  
Cell Types ◽  
Innate Immune ◽  
Host Cells ◽  
Experimental Systems ◽  
Monocytes And Macrophages ◽  
Review Reports

Coxiella burnetii is an obligate intracellular Gram-negative bacterium and the causative agent of a worldwide zoonosis known as Q fever. The pathogen invades monocytes and macrophages, replicating within acidic phagolysosomes and evading host defenses through different immune evasion strategies that are mainly associated with the structure of its lipopolysaccharide. The main transmission routes are aerosols and ingestion of fomites from infected animals. The innate immune system provides the first host defense against the microorganism, and it is crucial to direct the infection towards a self-limiting respiratory disease or the chronic form. This review reports the advances in understanding the mechanisms of innate immunity acting during C. burnetii infection and the strategies that pathogen put in place to infect the host cells and to modify the expression of specific host cell genes in order to subvert cellular processes. The mechanisms through which different cell types with different genetic backgrounds are differently susceptible to C. burnetii intracellular growth are discussed. The subsets of cytokines induced following C. burnetii infection as well as the pathogen influence on an inflammasome-mediated response are also described. Finally, we discuss the use of animal experimental systems for studying the innate immune response against C. burnetii and discovering novel methods for prevention and treatment of disease in humans and livestock.

scholarly journals Inflammasome Activation in Response to the Yersinia Type III Secretion System Requires Hyperinjection of Translocon Proteins YopB and YopD

mBio ◽  
2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Erin E. Zwack ◽  
Annelise G. Snyder ◽  
Meghan A. Wynosky-Dolfi ◽  
Gordon Ruthel ◽  
Naomi H. Philip ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Type Iii Secretion ◽  
Yersinia Pseudotuberculosis ◽  
Innate Immune ◽  
Target Cells ◽  
Inflammasome Activation ◽  
Secretion Systems ◽  
Type Iii ◽  
Infected Cells

ABSTRACTType III secretion systems (T3SS) translocate effector proteins into target cells in order to disrupt or modulate host cell signaling pathways and establish replicative niches. However, recognition of T3SS activity by cytosolic pattern recognition receptors (PRRs) of the nucleotide-binding domain leucine rich repeat (NLR) family, either through detection of translocated products or membrane disruption, induces assembly of multiprotein complexes known as inflammasomes. Macrophages infected withYersinia pseudotuberculosisstrains lacking all known effectors or lacking the translocation regulator YopK induce rapid activation of both the canonical NLRP3 and noncanonical caspase-11 inflammasomes. While this inflammasome activation requires a functional T3SS, the precise signal that triggers inflammasome activation in response to Yersinia T3SS activity remains unclear. Effectorless strains of Yersinia as well as ΔyopKstrains translocate elevated levels of T3SS substrates into infected cells. To dissect the contribution of pore formation and translocation to inflammasome activation, we took advantage of variants of YopD and LcrH that separate these functions of the T3SS. Notably, YopD variants that abrogated translocation but not pore-forming activity failed to induce inflammasome activation. Furthermore, analysis of individual infected cells revealed that inflammasome activation at the single-cell level correlated with translocated levels of YopB and YopD themselves. Intriguingly, LcrH mutants that are fully competent for effector translocation but produce and translocate lower levels of YopB and YopD also fail to trigger inflammasome activation. Our findings therefore suggest that hypertranslocation of YopD and YopB is linked to inflammasome activation in response to the Yersinia T3SS.IMPORTANCEThe innate immune response is critical to effective clearance of pathogens. Recognition of conserved virulence structures and activities by innate immune receptors such as NLRs constitute one of the first steps in mounting the innate immune response. However, pathogens such as Yersinia actively evade or subvert components of host defense, such as inflammasomes. The T3SS-secreted protein YopK is an essential virulence factor that limits translocation of other Yops, thereby limiting T3SS-induced inflammasome activation. However, what triggers inflammasome activation in cells infected by YopK-deficient Yersinia is not clear. Our findings indicate that hypertranslocation of pore complex proteins promotes inflammasome activation and that YopK prevents inflammasome activation by the T3SS by limiting translocation of YopD and YopB themselves.

scholarly journals Viral Modulation of TLRs and Cytokines and the Related Immunotherapies for HPV-Associated Cancers

2018 ◽  
Vol 2018 ◽  
pp. 1-17 ◽  
Author(s):  
Marconi Rego Barros ◽  
Talita Helena Araújo de Oliveira ◽  
Cristiane Moutinho Lagos de Melo ◽  
Aldo Venuti ◽  
Antonio Carlos de Freitas
Keyword(s):  
Immune Response ◽  
Human Papillomavirus ◽  
Immune System ◽  
Immune Evasion ◽  
Innate Immune System ◽  
Innate Immune ◽  
Cell Maturation ◽  
Host Immune System ◽  
Key Factor ◽  
Infected Cells

The modulation of the host innate immune system is a well-established carcinogenesis feature of several tumors, including human papillomavirus- (HPV-) related cancers. This virus is able to interrupt the initial events of the immune response, including the expression of Toll-like receptors (TLRs), cytokines, and inflammation. Both TLRs and cytokines play a central role in HPV recognition, cell maturation and differentiation as well as immune signalling. Therefore, the imbalance of this sensitive control of the immune response is a key factor for developing immunotherapies, which strengthen the host immune system to accomplish an efficient defence against HPV and HPV-infected cells. Based on this, the review is aimed at exposing the HPV immune evasion mechanisms involving TLRs and cytokines and at discussing existing and potential immunotherapeutic TLR- and cytokine-related tools.

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