scholarly journals Nivolumab augments antitumor activity of invariant natural killer T cells

2020 ◽  
Author(s):  
Mami Negawa ◽  
Fumie Ihara ◽  
Shinichiro Motohashi
Keyword(s):  
T Cell ◽  
Natural Killer ◽  
Treatment Options ◽  
Killer Cell ◽  
Cell Activity ◽  
A549 Cells ◽  
Nkt Cells ◽  
Nkt Cell ◽  
Cell Functions ◽  
Natural Killer T

Abstract Objective: Programmed death-1 (PD-1) negatively regulates T cell functions. Nivolumab is a clinically approved anti-PD-1 antibody that inhibits PD-1 signaling, thus enhancing T cell activity. Although nivolumab has been widely used in the treatment of various cancers, it is only effective in limited patients. To develop better treatment options, combination therapies with nivolumab have been in the spotlight. Natural killer T (NKT) cell-based immunotherapy involves activation of NKT cells by injection of ligand-loaded dendritic cells, thereby inducing antitumor immunity. In this study, we examined whether nivolumab treatment enhances NKT cell activity in tumor immunity to investigate the potential use of nivolumab in NKT cell-based immunotherapy as a combination therapy to improve the current treatment options. Results: PD-1 expression in NKT cells was upregulated in response to T cell receptor stimulation. Although nivolumab treatment had no impact on NKT cell proliferation, nivolumab-treated NKT cells exhibited increased production of cytokines and Granzyme B. Furthermore, nivolumab treatment significantly enhanced the cytotoxic activity of NKT cells against K562 or A549 cells and had an adjuvant effect on natural killer cell function. Taken together, these data indicate that combination of NKT cell-based immunotherapy and nivolumab treatment could be a better treatment option for various cancer.

scholarly journals Liver X receptors regulate natural killer T cell population and antitumor activity in the liver of mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kaori Endo-Umeda ◽  
Hiroyuki Nakashima ◽  
Shigeyuki Uno ◽  
Shota Toyoshima ◽  
Naoki Umeda ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Natural Killer ◽  
Cytokine Production ◽  
Nkt Cells ◽  
Inkt Cell ◽  
Cell Mediated Immunity ◽  
Inkt Cells ◽  
Nkt Cell ◽  
Natural Killer T

AbstractThe nuclear receptors liver X receptor α (LXRα) and LXRβ are lipid sensors that regulate lipid metabolism and immunity. Natural killer T (NKT) cells, a T cell subset expressing surface markers of both natural killer cells and T lymphocytes and involved in antitumor immunity, are another abundant immune cell type in the liver. The potential function of the metabolic regulators LXRα/β in hepatic NKT cells remains unknown. In this study, we examined the role of LXRα and LXRβ in NKT cells using mice deficient for LXRα and/or LXRβ, and found that hepatic invariant NKT (iNKT) cells are drastically decreased in LXRα/β-KO mice. Cytokine production stimulated by the iNKT cell activator α-galactosylceramide was impaired in LXRα/β-KO hepatic mononuclear cells and in LXRα/β-KO mice. iNKT cell-mediated antitumor effect was also disturbed in LXRα/β-KO mice. LXRα/β-KO mice transplanted with wild-type bone marrow showed decreased iNKT cells in the liver and spleen. The thymus of LXRα/β-KO mice showed a decreased population of iNKT cells. In conclusion, LXRα and LXRβ are essential for NKT cell-mediated immunity, such as cytokine production and hepatic antitumor activity, and are involved in NKT cell development in immune tissues, such as the thymus.

scholarly journals Chewing the fat on natural killer T cell development

2006 ◽  
Vol 203 (10) ◽  
pp. 2229-2232 ◽  
Author(s):  
Dale I. Godfrey ◽  
Malcolm J. McConville ◽  
Daniel G. Pellicci
Keyword(s):  
Natural Killer ◽  
Lysosomal Storage Diseases ◽  
Nkt Cells ◽  
Cell Development ◽  
Lysosomal Storage ◽  
Nkt Cell ◽  
Diverse Range ◽  
Natural Killer T Cell ◽  
New Evidence ◽  
Natural Killer T

Natural killer T cells (NKT cells) are selected in the thymus by self-glycolipid antigens presented by CD1d molecules. It is currently thought that one specific component of the lysosomal processing pathway, which leads to the production of isoglobotrihexosylceramide (iGb3), is essential for normal NKT cell development. New evidence now shows that NKT cell development can be disrupted by a diverse range of mutations that interfere with different elements of the lysosomal processing and degradation of glycolipids. This suggests that lysosomal storage diseases (LSDs) in general, rather than one specific defect, can disrupt CD1d antigen presentation, leading to impaired development of NKT cells.

scholarly journals Mechanisms of Innate Lymphoid Cell and Natural Killer T Cell Activation during Mucosal Inflammation

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
David Nau ◽  
Nora Altmayer ◽  
Jochen Mattner
Keyword(s):  
T Cell ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Adaptive Immune System ◽  
Nkt Cells ◽  
Lymphoid Cells ◽  
Mucosal Inflammation ◽  
Natural Killer T

Mucosal surfaces in the airways and the gastrointestinal tract are critical for the interactions of the host with its environment. Due to their abundance at mucosal tissue sites and their powerful immunomodulatory capacities, the role of innate lymphoid cells (ILCs) and natural killer T (NKT) cells in the maintenance of mucosal tolerance has recently moved into the focus of attention. While NKT cells as well as ILCs utilize distinct transcription factors for their development and lineage diversification, both cell populations can be further divided into three polarized subpopulations reflecting the distinction into Th1, Th2, and Th17 cells in the adaptive immune system. While bystander activation through cytokines mediates the induction of ILC and NKT cell responses, NKT cells become activated also through the engagement of their canonical T cell receptors (TCRs) by (glyco)lipid antigens (cognate recognition) presented by the atypical MHC I like molecule CD1d on antigen presenting cells (APCs). As both innate lymphocyte populations influence inflammatory responses due to the explosive release of copious amounts of different cytokines, they might represent interesting targets for clinical intervention. Thus, we will provide an outlook on pathways that might be interesting to evaluate in this context.

Changes of Immunoregulatory Cells Associated with Psychological Stress and Humor

1997 ◽  
Vol 84 (3_suppl) ◽  
pp. 1296-1298 ◽  
Author(s):  
Tsutomu Kamei ◽  
Hiroaki Kumano ◽  
Sumio Masumura
Keyword(s):  
T Cell ◽  
Natural Killer Cell ◽  
Natural Killer ◽  
Psychological Stress ◽  
Natural Killer Cell Activity ◽  
Killer Cell ◽  
Cell Activity ◽  
T Cell Subsets ◽  
Killer Cell Activity ◽  
Before And After

For 8 medical students influences of psychological stress or humor on T-cell subset percentages and natural killer cell activity were investigated by measuring these parameters before and after an examination and before and after watching a comedy video. Although T-cell subsets were not significantly affected by either stimulus and natural killer cell activity was not affected by the examination, the latter was significantly decreased after watching the comedy video.

scholarly journals Natural killer T-cell autoreactivity leads to a specialized activation state

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 4128-4138 ◽  
Author(s):  
Xiaohua Wang ◽  
Xiuxu Chen ◽  
Lance Rodenkirch ◽  
William Simonson ◽  
Sarah Wernimont ◽  
...  
Keyword(s):  
Natural Killer ◽  
Mapk Pathway ◽  
Nkt Cells ◽  
Interferon Γ ◽  
Janus Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Calcium Flux ◽  
Nkt Cell ◽  
Ifn Γ ◽  
Natural Killer T

Abstract Natural killer T (NKT) cells are innate-like T cells that recognize specific microbial antigens and also display autoreactivity to self-antigens. The nature of NKT-cell autoreactive activation remains poorly understood. We show here that the mitogen-activated protein kinase (MAPK) pathway is operative during human NKT-cell autoreactive activation, but calcium signaling is severely impaired. This results in a response that is biased toward granulocyte macrophage colony-stimulating factor (GM-CSF) secretion because this cytokine requires extracellular signal-regulated kinase (ERK) signaling but is not highly calcium dependent, whereas interferon-γ (IFN-γ), interleukin (IL)–4, and IL-2 production are minimal. Autoreactive activation was associated with reduced migration velocity but did not induce arrest; thus, NKT cells retained the ability to survey antigen presenting cells (APCs). IL-12 and IL-18 stimulated autoreactively activated NKT cells to secrete IFN-γ, and this was mediated by Janus kinase-signal transducers and activators of transcription (JAK-STAT)–dependent signaling without induction of calcium flux. This pathway did not require concurrent contact with CD1d+ APCs but was strictly dependent on preceding autoreactive stimulation that induced ERK activation. In contrast, NKT-cell responses to the glycolipid antigen α-galactosyl ceramide (α-GalCer) were dampened by prior autoreactive activation. These results show that NKT-cell autoreactivity induces restricted cytokine secretion and leads to altered basal activation that potentiates innate responsiveness to costimulatory cytokines while modulating sensitivity to foreign antigens.

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 SLAM Family Receptors Regulate Immunity with and without SAP-related Adaptors

2004 ◽  
Vol 199 (9) ◽  
pp. 1175-1178 ◽  
Author(s):  
André Veillette
Keyword(s):  
T Cell ◽  
Natural Killer Cell ◽  
Natural Killer ◽  
Killer Cell ◽  
Lymphocyte Activation ◽  
Definitive Evidence ◽  
Cell Functions ◽  
Slam Family ◽  
Immune Phenotypes

Two papers describing mice deficient in signaling lymphocyte activation molecule and 2B4 represent the first accounts of immune phenotypes in animals lacking members of the SLAM family of receptors. The findings provide definitive evidence of the importance of SLAM-related receptors in the regulation of T cell, macrophage, and natural killer cell functions.

scholarly journals Resistance of Natural Killer T Cell–Deficient Mice to Systemic Shwartzman Reaction

2000 ◽  
Vol 192 (11) ◽  
pp. 1645-1652 ◽  
Author(s):  
Francesco Dieli ◽  
Guido Sireci ◽  
Domenica Russo ◽  
Masaru Taniguchi ◽  
Juraj Ivanyi ◽  
...  
Keyword(s):  
Natural Killer ◽  
Severe Combined Immunodeficiency ◽  
Nkt Cells ◽  
Nkt Cell ◽  
Natural Killer T Cell ◽  
Shwartzman Reaction ◽  
Ifn Γ ◽  
High Doses ◽  
Deficient Mice ◽  
Natural Killer T

The generalized Shwartzman reaction in mice which had been primed and challenged with lipopolysaccharide (LPS) depends on interleukin (IL)-12–induced interferon (IFN)-γ production at the priming stage. We examined the involvement in the priming mechanism of the unique population of Vα14 natural killer T (NKT) cells because they promptly produce IFN-γ after IL-12 stimulation. We report here that LPS- or IL-12–primed NKT cell genetically deficient mice were found to be resistant to LPS-elicited mortality. This outcome can be attributed to the reduction of IFN-γ production, because injection of recombinant mouse IFN-γ, but not injection of IL-12, effectively primed the NKT cell–deficient mice. However, priming with high doses of LPS caused mortality of severe combined immunodeficiency, NKT cell–deficient, and CD1-deficient mice, indicating a major contribution of NKT cells to the Shwartzman reaction elicited by low doses of LPS, whereas at higher doses of LPS NK cells play a prominent role. These results suggest that the numerically small NKT cell population of normal mice apparently plays a mandatory role in the priming stage of the generalized Shwartzman reaction.

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