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 Distinct bioenergetic features of human invariant natural killer T (iNKT) cells enable retained functions in nutrient-deprived states

2021 ◽  
Author(s):  
Priya Khurana ◽  
Chakkapong Burudpakdee ◽  
Stephan A. Grupp ◽  
Ulf H. Beier ◽  
David M. Barrett ◽  
...  
Keyword(s):  
Natural Killer ◽  
Metabolic Flux ◽  
Cytokine Production ◽  
Inkt Cell ◽  
Flux Analysis ◽  
Inkt Cells ◽  
Effector Functions ◽  
Functional Features ◽  
Invariant Natural Killer ◽  
Natural Killer T

ABSTRACTInvariant natural killer T (iNKT) cells comprise a unique subset of lymphocytes that are primed for activation and possess innate NK-like functional features. Currently, iNKT cell-based immunotherapies remain in early clinical stages, and little is known about the ability of these cells to survive and retain effector functions within the solid tumor microenvironment (TME) long-term. In conventional T cells (TCONV), cellular metabolism is linked to effector functions and their ability to adapt to the nutrient-poor TME. In contrast, the bioenergetic requirements of iNKT cells – particularly those of human iNKT cells – at baseline and upon stimulation are not well understood; neither is how these requirements affect cytokine production or anti-tumor effector functions. We find that unlike TCONV, human iNKT cells are not dependent upon glucose or glutamine for cytokine production and cytotoxicity upon stimulation with anti-CD3 and anti-CD28. Additionally, transcriptional profiling revealed that stimulated human iNKT cells are less glycolytic than TCONV and display higher expression of fatty acid oxidation (FAO) and adenosine monophosphate-activated protein kinase (AMPK) pathway genes. Furthermore, stimulated iNKT cells displayed higher mitochondrial mass and membrane potential relative to TCONV. Real-time Seahorse metabolic flux analysis revealed that stimulated human iNKT cells utilize fatty acids as substrates for oxidation more than stimulated TCONV. Together, our data suggest that human iNKT cells possess different bioenergetic requirements from TCONV and display a more memory-like metabolic program relative to effector TCONV. Importantly, iNKT cell-based immunotherapeutic strategies could co-opt such unique features of iNKT cells to improve their efficacy and longevity of anti-tumor responses.

scholarly journals Natural Killer T Cell Ligand α-Galactosylceramide Enhances Protective Immunity Induced by Malaria Vaccines

2002 ◽  
Vol 195 (5) ◽  
pp. 617-624 ◽  
Author(s):  
Gloria Gonzalez-Aseguinolaza ◽  
Luc Van Kaer ◽  
Cornelia C. Bergmann ◽  
James M. Wilson ◽  
John Schmieg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Natural Killer ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Viral Infections ◽  
Tumor Development ◽  
Nkt Cells ◽  
Cell Mediated Immunity ◽  
Natural Killer T

The important role played by CD8+ T lymphocytes in the control of parasitic and viral infections, as well as tumor development, has raised the need for the development of adjuvants capable of enhancing cell-mediated immunity. It is well established that protective immunity against liver stages of malaria parasites is primarily mediated by CD8+ T cells in mice. Activation of natural killer T (NKT) cells by the glycolipid ligand, α-galactosylceramide (α-GalCer), causes bystander activation of NK, B, CD4+, and CD8+ T cells. Our study shows that coadministration of α-GalCer with suboptimal doses of irradiated sporozoites or recombinant viruses expressing a malaria antigen greatly enhances the level of protective anti-malaria immunity in mice. We also show that coadministration of α-GalCer with various different immunogens strongly enhances antigen-specific CD8+ T cell responses, and to a lesser degree, Th1-type responses. The adjuvant effects of α-GalCer require CD1d molecules, Vα14 NKT cells, and interferon γ. As α-GalCer stimulates both human and murine NKT cells, these findings should contribute to the design of more effective vaccines against malaria and other intracellular pathogens, as well as tumors.

scholarly journals Graft invariant natural killer T-cell dose predicts risk of acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation

Blood ◽  
2012 ◽  
Vol 119 (21) ◽  
pp. 5030-5036 ◽  
Author(s):  
Aristeidis Chaidos ◽  
Scott Patterson ◽  
Richard Szydlo ◽  
Mohammed Suhail Chaudhry ◽  
Francesco Dazzi ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Natural Killer ◽  
Inkt Cell ◽  
Inkt Cells ◽  
Cell Dose ◽  
Grade Ii ◽  
Clinically Significant ◽  
Invariant Natural Killer ◽  
Natural Killer T

Abstract Invariant natural killer T (iNKT) cells are powerful immunomodulatory cells that in mice regulate a variety of immune responses, including acute GVHD (aGVHD). However, their clinical relevance and in particular their role in clinical aGVHD are not known. We studied whether peripheral blood stem cell (PBSC) graft iNKT-cell dose affects on the occurrence of clinically significant grade II-IV aGVHD in patients (n = 57) undergoing sibling, HLA-identical allogeneic HSCT. In multivariate analysis, CD4− iNKT-cell dose was the only graft parameter to predict clinically significant aGVHD. The cumulative incidence of grade II-IV aGVHD in patients receiving CD4− iNKT-cell doses above and below the median were 24.2% and 71.4%, respectively (P = .0008); low CD4− iNKT-cell dose was associated with a relative risk of grade II-IV aGVHD of 4.27 (P = .0023; 95% CI, 1.68-10.85). Consistent with a role of iNKT cells in regulating aGVHD, in mixed lymphocyte reaction assays, CD4− iNKT cells effectively suppressed T-cell proliferation and IFN-γ secretion in a contact-dependent manner. In conclusion, higher doses of CD4− iNKT cells in PBSC grafts are associated with protection from aGVHD. This effect could be harnessed for prevention of aGVHD.

scholarly journals Combination of NKT14m and Low Dose IL-12 Promotes Invariant Natural Killer T Cell IFN-γ Production and Tumor Control

2020 ◽  
Vol 21 (14) ◽  
pp. 5085
Author(s):  
Peng Guan ◽  
Robert Schaub ◽  
Kim E. Nichols ◽  
Rupali Das
Keyword(s):  
T Cell ◽  
Natural Killer ◽  
Low Dose ◽  
Inkt Cell ◽  
Tumor Control ◽  
Inkt Cells ◽  
Ifn Γ ◽  
Invariant Natural Killer ◽  
Natural Killer T

Invariant natural killer T (iNKT) cells are innate-like T lymphocytes characterized by the expression of an invariant T cell receptor (iTCR) that recognizes glycolipid antigens presented by the MHC I-like CD1d molecule. Following antigenic stimulation, iNKT cells rapidly produce large amounts of cytokines that can trans-activate dendritic cells (DC) and promote the anti-tumor functions of cytotoxic lymphocytes, such as natural killer (NK) and CD8 T cells. Additionally, iNKT cells can mediate robust and direct cytotoxicity against CD1d+ tumor targets. However, many tumors down-regulate CD1d and evade iNKT cell attack. To circumvent this critical barrier to iNKT cell anti-tumor activity, a novel monoclonal antibody (mAb), NKT14 has been recently developed. This agonistic antibody binds directly and specifically to the iTCR of murine iNKT cells. In the current study, we demonstrate that NKT14m mediates robust activation, cytokine production and degranulation of murine iNKT cells, in vitro. Consistently, NKT14m also promoted iNKT cell activation and immunomodulatory functions, in vivo. Finally, administration of NKT14m with low dose interleukin (IL)-12 further augmented iNKT cell IFN-γ production in vivo, and this combination conferred superior suppression of tumor cell growth compared to NKT14m or IL-12 alone. Together, these data demonstrate that a combination treatment consisting of low dose IL-12 and iTCR-specific mAb may be an attractive alternative to activate iNKT cell anti-tumor functions.

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 Influence of Natural Killer Cells and Natural Killer T Cells on Periodontal Disease: A Systematic Review of the Current Literature

2020 ◽  
Vol 21 (24) ◽  
pp. 9766
Author(s):  
Andreas Seidel ◽  
Corinna L. Seidel ◽  
Matthias Weider ◽  
Rüdiger Junker ◽  
Lina Gölz ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Periodontal Disease ◽  
B Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Cytokine Production ◽  
Nkt Cells ◽  
Nkt Cell ◽  
Cell Crosstalk ◽  
Natural Killer T

Natural killer (NK) cells, as members of the innate immune system, and natural killer T (NKT) cells, bridging innate and adaptive immunity, play a prominent role in chronic inflammatory diseases and cancerogenesis, yet have scarcely been examined in oral diseases. Therefore, systematic research on the latest literature focusing on NK/NKT cell-mediated mechanisms in periodontal disease, including the time period 1988–2020, was carried out in MEDLINE (PubMed) using a predetermined search strategy, with a final selection of 25 studies. The results showed that NK cells tend to have rather proinflammatory influences via cytokine production, cytotoxic effects, dendritic-cell-crosstalk, and autoimmune reactions, while contrarily, NKT cell-mediated mechanisms were proinflammatory and immunoregulatory, ranging from protective effects via B-cell-regulation, specific antibody production, and the suppression of autoimmunity to destructive effects via cytokine production, dendritic-cell-crosstalk, and T-/B-cell interactions. Since NK cells seem to have a proinflammatory role in periodontitis, further research should focus on the proinflammatory and immunoregulatory properties of NKT cells in order to create, in addition to antibacterial strategies in dental inflammatory disease, novel anti-inflammatory therapeutic approaches modulating host immunity towards dental health.

scholarly journals Invariant and Noninvariant Natural Killer T Cells Exert Opposite Regulatory Functions on the Immune Response during Murine Schistosomiasis

2007 ◽  
Vol 75 (5) ◽  
pp. 2171-2180 ◽  
Author(s):  
Thierry Mallevaey ◽  
Josette Fontaine ◽  
Laetitia Breuilh ◽  
Christophe Paget ◽  
Alexandre Castro-Keller ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Differentiation ◽  
T Cell ◽  
Natural Killer ◽  
Egg Production ◽  
Phase 1 ◽  
Nkt Cells ◽  
Inkt Cells ◽  
Th1 Cell ◽  
Natural Killer T

ABSTRACT CD1d-restricted natural killer T (NKT) cells represent a heterogeneous population of innate memory immune cells expressing both NK and T-cell markers distributed into two major subsets, i.e., invariant NKT (iNKT) cells, which express exclusively an invariant T-cell receptor (TCR) α chain (Vα14Jα18 in mice), and non-iNKT cells, which express more diverse TCRs. NKT cells quickly produce Th1- and/or Th2-type cytokines following stimulation with glycolipid antigen (Ag) and, through this property, play potent immunoregulatory roles in autoimmune diseases, cancer, and infection. No study has addressed the role of NKT cells in metazoan parasite infections so far. We show that during murine schistosomiasis, the apparent frequency of both iNKT cells and non-iNKT cells decreased in the spleen as early as 3 weeks postinfection (p.i.) and that both populations expressed a greater amount of the activation marker CD69 at 6 weeks p.i., suggesting an activated phenotype. Two different NKT-cell-deficient mouse models, namely, TCR Jα18−/− (exclusively deficient in iNKT cells) and CD1d−/− (deficient in both iNKT and non-iNKT cells) mice, were used to explore the implication of these subsets in infection. We show that whereas both iNKT and non-iNKT cells do not have a major impact on the immune response during the early phase (1 and 4 weeks) of infection, they exert important, although opposite, effects on the immune response during the acute phase of the disease (7 and 12 weeks), after schistosome egg production. Indeed, iNKT cells contribute to Th1 cell differentiation whereas non-iNKT cells might be mostly implicated in Th2 cell differentiation in response to parasite Ag. Our findings suggest, for the first time, that helminths activate both iNKT and non-iNKT cells in vivo, enabling them to differentially influence the Th1/Th2 balance of the immune response.

scholarly journals Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection

2011 ◽  
Vol 208 (6) ◽  
pp. 1163-1177 ◽  
Author(s):  
Manfred Brigl ◽  
Raju V.V. Tatituri ◽  
Gerald F.M. Watts ◽  
Veemal Bhowruth ◽  
Elizabeth A. Leadbetter ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Constitutive Expression ◽  
Microbial Pathogens ◽  
Inkt Cell ◽  
Microbial Infection ◽  
Inkt Cells ◽  
Natural Killer T

Invariant natural killer T cells (iNKT cells) are critical for host defense against a variety of microbial pathogens. However, the central question of how iNKT cells are activated by microbes has not been fully explained. The example of adaptive MHC-restricted T cells, studies using synthetic pharmacological α-galactosylceramides, and the recent discovery of microbial iNKT cell ligands have all suggested that recognition of foreign lipid antigens is the main driver for iNKT cell activation during infection. However, when we compared the role of microbial antigens versus innate cytokine-driven mechanisms, we found that iNKT cell interferon-γ production after in vitro stimulation or infection with diverse bacteria overwhelmingly depended on toll-like receptor–driven IL-12. Importantly, activation of iNKT cells in vivo during infection with Sphingomonas yanoikuyae or Streptococcus pneumoniae, pathogens which are known to express iNKT cell antigens and which require iNKT cells for effective protection, also predominantly depended on IL-12. Constitutive expression of high levels of IL-12 receptor by iNKT cells enabled instant IL-12–induced STAT4 activation, demonstrating that among T cells, iNKT cells are uniquely equipped for immediate, cytokine-driven activation. These findings reveal that innate and cytokine-driven signals, rather than cognate microbial antigen, dominate in iNKT cell activation during microbial infections.

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 Type I Natural Killer T Cells as Key Regulators of the Immune Response to Infectious Diseases

2020 ◽  
Vol 34 (2) ◽  
pp. e00232-20
Author(s):  
Nicolás M. S. Gálvez ◽  
Karen Bohmwald ◽  
Gaspar A. Pacheco ◽  
Catalina A. Andrade ◽  
Leandro J. Carreño ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Infectious Diseases ◽  
Natural Killer ◽  
Nkt Cells ◽  
Interleukin 4 ◽  
Type I ◽  
Inkt Cells ◽  
Class I Mhc ◽  
Natural Killer T

SUMMARYThe immune system must work in an orchestrated way to achieve an optimal response upon detection of antigens. The cells comprising the immune response are traditionally divided into two major subsets, innate and adaptive, with particular characteristics for each type. Type I natural killer T (iNKT) cells are defined as innate-like T cells sharing features with both traditional adaptive and innate cells, such as the expression of an invariant T cell receptor (TCR) and several NK receptors. The invariant TCR in iNKT cells interacts with CD1d, a major histocompatibility complex class I (MHC-I)-like molecule. CD1d can bind and present antigens of lipid nature and induce the activation of iNKT cells, leading to the secretion of various cytokines, such as gamma interferon (IFN-γ) and interleukin 4 (IL-4). These cytokines will aid in the activation of other immune cells following stimulation of iNKT cells. Several molecules with the capacity to bind to CD1d have been discovered, including α-galactosylceramide. Likewise, several molecules have been synthesized that are capable of polarizing iNKT cells into different profiles, either pro- or anti-inflammatory. This versatility allows NKT cells to either aid or impair the clearance of pathogens or to even control or increase the symptoms associated with pathogenic infections. Such diverse contributions of NKT cells to infectious diseases are supported by several publications showing either a beneficial or detrimental role of these cells during diseases. In this article, we discuss current data relative to iNKT cells and their features, with an emphasis on their driving role in diseases produced by pathogenic agents in an organ-oriented fashion.

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