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 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.

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 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.

scholarly journals Natural killer T cells in lipoprotein metabolism and atherosclerosis

2011 ◽  
Vol 106 (11) ◽  
pp. 814-819 ◽  
Author(s):  
Godfrey Getz ◽  
Paul VanderLaan ◽  
Catherine Reardon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Natural Killer ◽  
Cell Receptor ◽  
Nkt Cells ◽  
Inflammatory Disorder ◽  
Chronic Inflammatory Disorder ◽  
Invariant Nkt Cells ◽  
Adaptive Immune ◽  
Natural Killer T

SummaryCells of both the innate and adaptive immune system participate in the development of atherosclerosis, a chronic inflammatory disorder of medium and large arteries. Natural killer T (NKT) cells express surface markers characteristic of natural killer cells and conventional T cells and bridge the innate and adaptive immune systems. The development and activation of NKT cells is dependent upon CD1d, a MHC-class I-type molecule that presents lipids, especially glycolipids to the T cell receptors on NKT cells. There are two classes of NKT cells; invariant NKT cells that express a semi-invariant T cell receptor and variant NKT cells. This review summarises studies in murine models in which the effect of the activation, overexpression or deletion of NKT cells or only invariant NKT cells on atherosclerosis has been examined.

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 Human invariant natural killer T cells promote tolerance by preferential apoptosis induction of conventional dendritic cells

Haematologica ◽  
2021 ◽  
Author(s):  
Hannes Schmid ◽  
Emmanuelle M. Ribeiro ◽  
Kathy-Ann Secker ◽  
Silke Duerr-Stoerzer ◽  
Hildegard Keppeler ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Inkt Cells ◽  
Healthy Donors ◽  
Invariant Natural Killer ◽  
Natural Killer T

Graft-versus-host disease (GvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. We recently showed in murine studies and in vitro human models that adoptively transferred invariant natural killer T (iNKT) cells protect from GvHD and promote graft-versus-leukemia effects. The cellular mechanisms underlying GvHD prevention by iNKT cells in humans, however, remain unknown. To study relevant cellular interactions, dendritic cells (DCs) were either generated from monocytes or isolated directly from blood of healthy donors or GvHD patients and co-cultured in a mixed lymphocyte reaction (MLR) with T cells obtained from healthy donors or transplantation bags. Addition of culture-expanded iNKT cells to the MLR induced DC apoptosis in a cell contact-dependent manner, thereby preventing T-cell activation and proliferation. Annexin V/PI staining and image stream assays showed that CD4+CD8-, CD4-CD8+ and double negative iNKT cells are similarly able to induce DC apoptosis. Further MLR assays revealed that conventional DCs (cDCs) but not plasmacytoid DCs (pDCs) could induce alloreactive T-cell activation and proliferation. Interestingly, cDCs were also more susceptible to apoptosis induced by iNKT cells, which correlates with their higher CD1d expression, leading to a bias in favor of pDCs. Remarkably, these results could also be observed in GvHD patients. We propose a new mechanism how ex vivo expanded human iNKT cells prevent alloreactivity of T cells. iNKT cells modulate T-cell responses by selective apoptosis of DC subsets, resulting in suppression of T-cell activation and proliferation while enabling beneficial immune responses through pDCs.

scholarly journals The Role of Langerin⁺ CD8α⁺ Dendritic Cells in Tumour Immunotherapy

2021 ◽  
Author(s):  
◽  
John David Gibbins
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Natural Killer ◽  
Cd8 T Cells ◽  
Suppressor Cells ◽  
Invariant Natural Killer ◽  
Natural Killer T

<p>The immune system has the potential to selectively target and eliminate tumours cells. However, the induction of an immunosuppressive environment by factors released by tumours cells, or by the tumour stroma, in combination with difficulties in differentiating between healthy and malignant cells, contributes to inefficient or disabled anti-tumour immune responses. A variety of different immunotherapeutic approaches are being developed to tip the balance in favour of anti-tumour immunity. Many of these approaches are designed to stimulate improved activity of T cells with specificity for tumour-associated antigens.  This thesis explores how T cell-mediated responses are initiated and maintained in immunotherapy, with an emphasis on the role of antigen presentation by resident dendritic cells (DCs). An animal model was used in which a DC subset in the spleen that expresses the cell marker langerin could be selectively ablated during the course of therapy. As these DCs have been shown to be uniquely capable of acquiring circulating antigens and cellular debris, and have a heightened capacity for cross-priming CD8⁺ T cells, it was hypothesised that the function of these cells could play a significant role in determining the outcome of immunotherapies.  A model of adoptive T cell therapy was examined in mice challenged with an intravenously administered lymphoma that formed tumour foci in a variety of locations in the body. Treating established tumours by adoptively transferring in vitro activated effector CD8⁺ T cells significantly increased their symptom-free survival. The protection received by this therapy was dependent on a stimulus being provided by endogenous langerin⁺ CD8α⁺ DCs to the transferred T cells. In the absence of langerin⁺ CD8α⁺ DCs, the proportion and number of transferred anti-tumour CD8⁺ T cells was lower in the blood and spleen. However, no obvious differences in phenotype and function could be defined. Langerin⁺ CD8α⁺ DCs therefore contribute to the maintenance of an effective CD8⁺ T cell-based immunotherapy and the role of endogenous DCs should be taken into consideration during the design of immunotherapies.  To investigate the role of langerin⁺ CD8α⁺ DCs in initiating effector T cell responses, a novel whole-cell vaccine was developed for the treatment of acute myeloid leukaemia (AML). This vaccine exploited the stimulatory functions of invariant natural killer T cells, and was therefore administered intravenously to access the large invariant natural killer T cell compartment of the spleen. The vaccine completely protected mice from developing leukaemia when challenged with AML cells after vaccination, with CD4⁺ and CD8⁺ T cells mediating protection. The immune response generated by the vaccine was shown to be completely dependent on langerin⁺ CD8α⁺ DCs. In hosts with established tumours; however, the vaccine was ineffective. This may have been partially due to a reduced function of langerin⁺ CD8α⁺ DCs as their activation phenotype was significantly reduced in the presence of established AML; however, non-specific T cells could still be stimulated via these DCs. Reduced vaccine efficacy was associated with increased number and/or function of suppressor cells, including regulatory T cells and myeloid derived suppressor cells within the host. In addition, in leukemic hosts, the proportion of T cells in the spleen was reduced, and the function of AML-specific CD4⁺ T cells, but not CD8⁺ T cells, was impaired. Driving AML-bearing hosts into remission with chemotherapy prior to vaccination enabled the vaccine to protect the host from subsequent AML challenge. Langerin⁺ CD8α⁺ DCs are therefore responsible for initiating the vaccine-induced immune response in this model and their suppression may have contributed to the inefficacy of the vaccine in the presence of established tumours.</p>

scholarly journals Invariant natural killer T cell–natural killer cell interactions dictate transplantation outcome after α-galactosylceramide administration

Blood ◽  
2009 ◽  
Vol 113 (23) ◽  
pp. 5999-6010 ◽  
Author(s):  
Rachel D. Kuns ◽  
Edward S. Morris ◽  
Kelli P. A. MacDonald ◽  
Kate A. Markey ◽  
Helen M. Morris ◽  
...  
Keyword(s):  
T Cell ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Type I ◽  
Inkt Cells ◽  
Invariant Natural Killer ◽  
Natural Killer T

Abstract Invariant natural killer T cells (iNKT cells) have pivotal roles in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects. iNKT cells are activated through their T-cell receptors by glycolipid moieties (typically the α-galactosylceramide [α-GalCer] derivative KRN7000) presented within CD1d. We investigated the ability of modified α-GalCer molecules to differentially modulate alloreactivity and GVL. KRN7000 and the N-acyl variant, C20:2, were administered in multiple well-established murine models of allogeneic stem cell transplantation. The highly potent and specific activation of all type I NKT cells with C20:2 failed to exacerbate and in most settings inhibited GVHD late after transplantation, whereas effects on GVL were variable. In contrast, the administration of KRN7000 induced hyperacute GVHD and early mortality in all models tested. Administration of KRN7000, but not C20:2, was found to result in downstream interleukin (IL)-12 and dendritic cell (DC)–dependent natural killer (NK)– and conventional T-cell activation. Specific depletion of host DCs, IL-12, or donor NK cells prevented this pathogenic response and the induction of hyperacute GVHD. These data demonstrate the ability of profound iNKT activation to modulate both the innate and adaptive immune response via the DC–NK-cell interaction and raise concern for the use of α-GalCer therapeutically to modulate GVHD and GVL effects.

scholarly journals Invariant Natural Killer T-Cells and Total CD1d Restricted Cells Differentially Influence Lipid Metabolism and Atherosclerosis in Low Density Receptor Deficient Mice

2019 ◽  
Vol 20 (18) ◽  
pp. 4566
Author(s):  
Paul A. VanderLaan ◽  
Catherine A. Reardon ◽  
Veneracion G. Cabana ◽  
Chyung-Ru Wang ◽  
Godfrey S. Getz
Keyword(s):  
Lipid Metabolism ◽  
Natural Killer ◽  
Plasma Lipids ◽  
Plasma Cholesterol ◽  
Atherosclerotic Lesion ◽  
Nkt Cells ◽  
Type I ◽  
Type Ii ◽  
Inkt Cells ◽  
Natural Killer T

Natural killer T (NKT) cells are a distinct subset of lymphocytes that bridge the innate and adaptive immune response and can be divided into type I invariant NKT cells (iNKT) and type II NKT cells. The objective of this study is to examine the effects of NKT cell on lipid metabolism and the initiation and progression of atherosclerosis in LDL receptor deficient (LDLR−/−) mice. Mice were fed an atherogenic diet for 4 or 8 weeks and plasma lipids, lipoproteins, and atherosclerosis were measured. The selective absence of iNKT cells in Jα18−/−LDLR−/− mice led to an increase in plasma cholesterol levels in female mice. Transgenic Vα14tg/LDLR−/− mice with elevated numbers of iNKT cells had increased late atherosclerosis of the innominate artery, though absence of either iNKT cells or all NKT cells and other CD1d expressing cells had varying effects on atherosclerotic lesion burden in the ascending aortic arch and aortic root. These studies not only highlight the potential modulatory role played by NKT cells in atherosclerosis and lipid metabolism, but also raise the possibility that divergent roles may be played by iNKT and CD1d restricted cells such as type II NKT cells or other CD1d expressing cells.

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