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.

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.

scholarly journals Concanavalin A-induced endocytosis in rabbit reticulocytes, and its decrease with reticulocyte maturation.

1979 ◽  
Vol 80 (2) ◽  
pp. 487-491 ◽  
Author(s):  
S Zweig ◽  
S J Singer
Keyword(s):  
Concanavalin A ◽  
Molecular Mechanisms ◽  
Limited Extent ◽  
Con A ◽  
Mature Erythrocyte ◽  
Thin Sections ◽  
Elimination Process ◽  
Transmission Electron ◽  
Reticulocyte Maturation ◽  
Rabbit Reticulocytes

Concanavalin A (Con A) was taken up to a limited extent by endocytosis in rabbit reticulocytes but not in rabbit erythrocytes. This process was observed by the use of ferritin-labeled Con A and transmission electron microscopy of thin sections of plastic-embedded cells. Furthermore, the extent of endocytosis among the reticulocytes decreased with the extent of their maturation, reticulocyte age being measured by ribosome configurations. These results are consistent with the proposal that there are domains in the membranes of reticulocytes in which the Con A receptors are laterally mobile, and can be clustered and endocytosed. These mobile domains exist, or are formed, within a larger framework of immobile membrane. During reticulocyte maturation, these domains are gradually eliminated, eventually disappearing upon formation of the mature erythrocyte. Possible molecular mechanisms for this proposed elimination process are discussed.

Trafficking machinery of NKT cells: shared and differential chemokine receptor expression among Vα24+Vβ11+ NKT cell subsets with distinct cytokine-producing capacity

Blood ◽  
2002 ◽  
Vol 100 (1) ◽  
pp. 11-16 ◽  
Author(s):  
Chang H. Kim ◽  
Brent Johnston ◽  
Eugene C. Butcher
Keyword(s):  
Chemokine Receptors ◽  
Expression Patterns ◽  
Interleukin 2 ◽  
Production Capacity ◽  
Nkt Cells ◽  
Receptor Expression ◽  
Interleukin 4 ◽  
Small Subset ◽  
Nkt Cell ◽  
Nonlymphoid Tissue

Abstract Natural killer T (NKT) cells are important regulators of the immune system, but their trafficking machinery, including expression of chemokine receptors, has been poorly defined. Unlike other conventional T-cell populations, we show that most NKT cells express receptors for extralymphoid tissue or inflammation-related chemokines (CCR2, CCR5, and CXCR3), while few NKT cells express lymphoid tissue–homing chemokine receptors (CCR7 and CXCR5). A population with homing potential for lymph nodes (L selectin+ CCR7+) exists only within a small subset of CD4 NKT cells. We show differential expression of chemokine receptors among NKT cell subsets: CCR4 is mainly expressed by a high cytokine (interleukin-4/interleukin-2)–producing (CD4) NKT subset, while CCR1, CCR6, and CXCR6 are preferentially expressed by the low cytokine-producing CD8 and CD4−CD8− subsets. In line with this, TARC/CCL17 (a CCR4 ligand) induces preferential chemotaxis of the CD4 NKT subset, while chemotactic activities of LARC/CCL20 (a CCR6 ligand) and MIP-1α/CCL3 (a CCR1 ligand) are focused on the CD8 and CD4−CD8− NKT cells. We conclude that, unlike conventional naive, memory, or effector T cells, the entire NKT cell population expresses nonlymphoid tissue homing chemokine receptors, yet NKT cell subsets differ considerably from each other by displaying distinct and reciprocal expression patterns of some chemokine receptors. Our results identify chemokine receptors that are potentially important for trafficking of human blood NKT cell subsets and reveal their function (cytokine production capacity)–dependent differential trafficking potentials.

scholarly journals Glucocorticoids induce the expression of CD8 alpha chains on concanavalin A-activated rat CD4+ T cells: induction is inhibited by rat recombinant interleukin 4.

1992 ◽  
Vol 176 (6) ◽  
pp. 1551-1559 ◽  
Author(s):  
F Ramirez ◽  
A J McKnight ◽  
A Silva ◽  
D Mason
Keyword(s):  
T Cells ◽  
T Cell ◽  
Concanavalin A ◽  
Cd4 T Cells ◽  
Interleukin 4 ◽  
Mrna Levels ◽  
Con A ◽  
Alpha Chain ◽  
T Cell Clone ◽  
Single Positive

Rat T lymphocytes, activated in vitro with concanavalin A (Con A), were shown by flow cytofluorographic analysis to contain a population of cells that simultaneously expressed CD4 and the alpha chain of CD8. The inclusion of the glucocorticoid hormone dexamethasone in the culture medium greatly increased both the frequency of these double-positive cells and the level of CD8 alpha chain expression. The level of expression of CD4 was not affected, and the cells that expressed CD8 antigen only also remained unchanged in surface phenotype. Detailed studies demonstrated unequivocally that the CD4+ CD8 alpha + cells were not artifacts produced by the random association of single-positive cells in the flow cytofluorograph, but arose from precursors that were single-positive CD4+ cells before activation. Furthermore, Con A activation of purified CD4+ T cells, in the presence of T cell-depleted accessory cells, showed that CD8+ T cells played no role in the induction process. However, the induction of CD8 alpha chain expression on CD4+ T cells and the enhancement of this expression by dexamethasone were almost completely inhibited by rat recombinant interleukin 4 (IL-4). Detection of mRNA for rat CD8 alpha chain by Northern blot closely paralleled the cell surface expression of CD8 alpha antigen, indicating that dexamethasone and IL-4 had opposing effects on mRNA levels. In contrast, IL-4 and dexamethasone both induced CD8 alpha chain expression on a rat CD4+ T cell clone when this was activated by specific antigen, and, although the effect with IL-4 was relatively weak, it did not antagonize the effect of the glucocorticoid. The possible significance of these results is briefly discussed.

scholarly journals Emodin Protects Against Concanavalin A-Induced Hepatitis in Mice Through Inhibiting Activation of the p38 MAPK-NF-κB Signaling Pathway

2015 ◽  
Vol 35 (4) ◽  
pp. 1557-1570 ◽  
Author(s):  
Jihua Xue ◽  
Feng Chen ◽  
Jing Wang ◽  
Shanshan Wu ◽  
Min Zheng ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Inflammatory Cytokines ◽  
Concanavalin A ◽  
Molecular Mechanisms ◽  
Hepatic Necrosis ◽  
Con A ◽  
Beneficial Effects ◽  
Cytokines And Chemokines ◽  
Before And After ◽  
Pro Inflammatory Cytokines

Background/Aims: To investigate the effects of emodin on concanavalin A (Con A)-induced hepatitis in mice and to elucidate its underlying molecular mechanisms. Methods: A fulminant hepatitis model was established successfully by the intravenous administration of Con A (20 mg/kg) to male Balb/c mice. Emodin was administered to the mice by gavage before and after Con A injection. The levels of pro-inflammatory cytokines and chemokines, numbers of CD4+ and F4/80+ cells infiltrated into the liver, and amounts of phosphorylated p38 MAPK and NF-γB in mouse livers and RAW264.7 and EL4 cells were measured. Results: Pretreatment with emodin significantly protected the animals from T cell-mediated hepatitis, as shown by the decreased elevations of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as reduced hepatic necrosis. In addition, emodin pretreatment markedly reduced the intrahepatic expression of pro-inflammatory cytokines and chemokines, including tumor necrosis factor (TNF)-a, interferon (IFN)-γ, interleukin (IL)-1ß, IL-6, IL-12, inducible nitric oxide synthase (iNOS), integrin alpha M (ITGAM), chemokine (C-C motif) ligand 2 (CCL2), macrophage inflammatory protein 2 (MIP-2) and chemokine (CXC motif) receptor 2 (CXCR2). Furthermore, emodin pretreatment dramatically suppressed the numbers of CD4+ and F4/80+ cells infiltrating into the liver as well as the activation of p38 MAPK and NF-γB in Con A-treated mouse livers and RAW264.7 and EL4 cells. Conclusion: The results indicate that emodin pretreatment protects against Con A-induced liver injury in mice; these beneficial effects may occur partially through inhibition of both the infiltration of CD4+ and F4/80+ cells and the activation of the p38 MAPK-NF-γB pathway in CD4+ T cells and macrophages.

Sequential production of interferon-γ by NK1.1+ T cells and natural killer cells is essential for the antimetastatic effect of α-galactosylceramide

Blood ◽  
2002 ◽  
Vol 99 (4) ◽  
pp. 1259-1266 ◽  
Author(s):  
Mark J. Smyth ◽  
Nadine Y. Crowe ◽  
Daniel G. Pellicci ◽  
Konstantinos Kyparissoudis ◽  
Janice M. Kelly ◽  
...  
Keyword(s):  
Nk Cells ◽  
Fas Ligand ◽  
Nkt Cells ◽  
Interferon Γ ◽  
Tumor Rejection ◽  
Interleukin 12 ◽  
Nkt Cell ◽  
Antimetastatic Activity ◽  
Antimetastatic Effect ◽  
Ifn Γ

The antimetastatic effect of the CD1d-binding glycolipid, α-galactosylceramide (α-GalCer), is mediated by NK1.1+T (NKT) cells; however, the mechanisms behind this process are poorly defined. Although it has been shown to involve NK cells and interferon-γ (IFN-γ) production, the way these factors collaborate to mediate effective tumor rejection and the importance of other factors characteristic of NKT cell and NK cell activation are unknown. Using gene-targeted mice and antibody treatments, the critical need for interleukin 12 (IL-12), IFN-γ, and NK cells has been shown in the antimetastatic activity of α-GalCer in the lungs and the liver. By contrast, in lung and liver metastasis models, cytotoxic molecules expressed by NK cells and NKT cells (perforin, Fas ligand, and tumor necrosis factor-related apoptosis-inducing ligand) and an NKT cell-secreted cytokine, IL-4, were not necessary for the antitumor activity of α-GalCer. Like IL-12, IL-18 was required for optimal serum IFN-γ induction and control of lung metastases by α-GalCer. IL-18 was unnecessary for α-GalCer–related suppression of liver metastases. Most importantly, after adoptive transfer of α-GalCer–reactive NKT cells or NK cells into NKT cell-deficient, IFN-γ–deficient, or RAG-1–deficient mice, it was demonstrated that the sequential production of IFN-γ by NKT cells and NK cells was absolutely required to reconstitute the antimetastatic activity of α-GalCer.

Generation of functional NKT cells in vitro from embryonic stem cells bearing rearranged invariant Vα14-Jα18 TCRα gene

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. 230-237 ◽  
Author(s):  
Hiroshi Watarai ◽  
Andrei Rybouchkin ◽  
Naomi Hongo ◽  
Yuko Nagata ◽  
Sakura Sakata ◽  
...  
Keyword(s):  
Culture System ◽  
Es Cells ◽  
Embryonic Stem ◽  
Nkt Cells ◽  
Interleukin 4 ◽  
Nkt Cell ◽  
Adjuvant Activity ◽  
Cell Potential

Abstract Establishment of a system with efficient generation of natural killer T (NKT) cells from embryonic stem (ES) cells would enable us to identify the cells with NKT-cell potential and obtain NKT cells with desired function. Here, using cloned ES (NKT-ES) cells generated by the transfer of nuclei from mature NKT cells, we have established a culture system that preferentially developed functional NKT cells and also identified early NKT progenitors, which first appeared on day 11 as a c-kit+ population in the cocultures on OP9 cells with expression of Notch ligand, delta-like1 (OP9/Dll-1) and became c-kitlo/− on day 14. Interestingly, in the presence of Notch signals, NKT-ES cells differentiated only to thymic CD44lo CD24hi NKT cells producing mainly interleukin-4 (IL-4), whereas NKT cells resembling CD44hi CD24lo liver NKT cells producing mainly interferon γ (IFN-γ) and exhibiting strong adjuvant activity in vivo were developed in the switch culture starting at day 14 in the absence of Notch. The cloned ES culture system offers a new opportunity for the elucidation of the molecular events on NKT-cell development and for the establishment of NKT-cell therapy.

A Small-Molecule Bcl-2 Inhibitor Amplifies NKT-Cell Killing of U937 Lymphoma Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1399-1399
Author(s):  
Jason Lickliter ◽  
Joanne Cox ◽  
Mie Nieda ◽  
Henry Lin ◽  
Andrew Nicol
Keyword(s):  
Small Molecule ◽  
Magnetic Beads ◽  
Fas Ligand ◽  
Immune Therapy ◽  
Single Agent ◽  
Annexin V ◽  
Nkt Cells ◽  
Target Cells ◽  
U937 Cells ◽  
Nkt Cell

Abstract Invariant Vα24+ Vβ11+ NKT cells regulate immune responses and are capable of direct cytotoxic activity against tumour-cell targets mediated via the perforin/granzyme-B, Fas ligand and TRAIL pathways. A potential mechanism for tumours to escape immune killing is to block downstream apoptotic pathways by overexpression of the Bcl-2 oncoprotein. We therefore evaluated whether the Bcl-2-expressing U937 lymphoma line could be sensitized to NKT-cell cytotoxicity by coexposure to the HA14-1 small-molecule Bcl-2 inhibitor. Vα24+ NKT cells were purified from donor blood samples using magnetic beads and activated by exposure to KRN7000 and IL-2. U937 cells were labelled with the PKH26 membrane dye and then cocultured with activated NKT cells in a 10:1 or 20:1 effector: target ratio in U-bottomed 96-well plates. Cultures were performed in the presence or absence of HA14-1. After 4 hours, the cells were stained with annexin V-FITC and analysed by flow cytometry. Apoptotic and viable target cells were quantified as annexin-V positive and negative cells, respectively, in the PKH26-positive gate. Results of experiments on NKT cells derived from 3 donors are shown in the figure. Bars represent the mean percentage of viable U937 cells in triplicate assays and error bars indicate the SD. At the concentration of HA14-1 used, there was only minor single-agent cytotoxicity. However, a significant increase in U937 apoptosis was observed with the combination of HA14-1 and NKT cells compared to NKT cells alone. We conclude that the addition of the HA14-1 Bcl-2 inhibitor significantly increases the cytotoxicity of NKT cells against U937 lymphoma targets. This provides preliminary data supporting the possibility that the use of a combination of a small molecule inhibitor with immune therapy may increase the clinical efficacy of immune therapies that work via cytotoxic killing of malignant targets. Figure Figure

scholarly journals Host natural killer T cells induce an interleukin-4–dependent expansion of donor CD4+CD25+Foxp3+ T regulatory cells that protects against graft-versus-host disease

Blood ◽  
2009 ◽  
Vol 113 (18) ◽  
pp. 4458-4467 ◽  
Author(s):  
Asha B. Pillai ◽  
Tracy I. George ◽  
Suparna Dutt ◽  
Samuel Strober
Keyword(s):  
T Cells ◽  
T Regulatory Cells ◽  
Natural Killer T Cells ◽  
Nkt Cells ◽  
Interleukin 4 ◽  
Regulatory Cells ◽  
Nkt Cell ◽  
Graft Versus Host ◽  
Killer T Cells

Abstract Although CD4+CD25+ T cells (T regulatory cells [Tregs]) and natural killer T cells (NKT cells) each protect against graft-versus-host disease (GVHD), interactions between these 2 regulatory cell populations after allogeneic bone marrow transplantation (BMT) have not been studied. We show that host NKT cells can induce an in vivo expansion of donor Tregs that prevents lethal GVHD in mice after conditioning with fractionated lymphoid irradiation (TLI) and anti–T-cell antibodies, a regimen that models human GVHD-protective nonmyeloablative protocols using TLI and antithymocyte globulin (ATG), followed by allogeneic hematopoietic cell transplantation (HCT). GVHD protection was lost in NKT-cell–deficient Jα18−/− hosts and interleukin-4 (IL-4)−/− hosts, or when the donor transplant was Treg depleted. Add-back of donor Tregs or wild-type host NKT cells restored GVHD protection. Donor Treg proliferation was lost in IL-4−/− hosts or when IL-4−/− mice were used as the source of NKT cells for adoptive transfer, indicating that host NKT cell augmentation of donor Treg proliferation after TLI/antithymocyte serum is IL-4 dependent. Our results demonstrate that host NKT cells and donor Tregs can act synergistically after BMT, and provide a mechanism by which strategies designed to preserve host regulatory cells can augment in vivo donor Treg expansion to regulate GVHD after allogeneic HCT.

Toll-like receptor 2 signaling is important for fas ligand on NKT cells, may contribute to liver injury induced by Salmonella infection

2001 ◽  
Vol 120 (5) ◽  
pp. A357-A357
Author(s):  
H SHIMIZU ◽  
Y FUKUDA ◽  
I NAKANO ◽  
Y KATANO ◽  
K NAGANO ◽  
...  
Keyword(s):  
Liver Injury ◽  
Fas Ligand ◽  
Nkt Cells ◽  
Toll Like Receptor ◽  
Salmonella Infection ◽  
Toll Like Receptor 2
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