Natural killer T (NKT) cells accelerate Shiga toxin type 2 (Stx2) pathology in mice

Mouse and human natural killer T (NKT) cells recognize a restricted set of glycosphingolipids presented by CD1d molecules, including self iGb3 and microbial α-glycuronosylceramides. The importance of the canonical Vα14-Jα18 TCR α chain for antigen recognition by NKT cells is well recognized, but the mechanisms underlying the Vβ8, Vβ7, and Vβ2 bias in mouse have not been explored. To study the influences of thymic selection and the constraints of pairing with Vα14-Jα18, we have created a population of mature T cells expressing Vα14-Jα18 TCR α chain in CD1d-deficient mice and studied its recognition properties in vitro and in vivo. Transgenic cells expressed a diverse Vβ repertoire but their recognition of endogenous ligands and synthetic iGb3 was restricted to the same biased Vβ repertoire as expressed in natural NKT cells. In contrast, α-GalCer, a synthetic homologue of microbial α-glycuronosylceramides, was recognized by a broader set of Vβ chains, including the biased NKT set but also Vβ6, Vβ9, Vβ10, and Vβ14. These surprising findings demonstrate that, whereas Vβ8, Vβ7, and Vβ2 represent the optimal solution for recognition of endogenous ligand, many Vβ chains that are potentially useful for the recognition of foreign lipids fail to be selected in the NKT cell repertoire.

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Chewing the fat on natural killer T cell development

Journal of Experimental Medicine ◽

10.1084/jem.20061787 ◽

2006 ◽

Vol 203 (10) ◽

pp. 2229-2232 ◽

Cited By ~ 23

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.

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Abstract 039: Natural Killer T Cells Play Protective Roles in Cardiovirus-Induced Myocarditis by Inducing Anti-Viral and Regulatory Cytokines

Circulation Research ◽

10.1161/res.113.suppl_1.a039 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Fumitaka Sato ◽

Seiichi Omura ◽

Nicholas E Martinez ◽

Eiichiro Kawai ◽

Sadie F Pearson ◽

...

Keyword(s):

Natural Killer ◽

Acute Phase ◽

Viral Myocarditis ◽

Chronic Phase ◽

Nkt Cells ◽

Viral Clearance ◽

Left Ventricular Ejection ◽

Ifn Γ ◽

Anti Inflammatory ◽

Natural Killer T

Picornavirus infections have been known as a leading cause of viral myocarditis in humans. Theiler’s murine encephalomyelitis virus (TMEV) belongs to the genus Cardiovirus, the family Picornaviridae, and can cause myocarditis in susceptible mice. In viral myocarditis, viral replication in the heart and/or immune responses against virus as well as cardiac antigens (autoimmunity) can contribute to the pathogenesis. Natural killer T (NKT) cells can play a regulatory role in viral infections by producing anti-viral and anti-inflammatory cytokines; interferon (IFN)-γ can contribute to either viral clearance or tissue damage (immunopathology), while anti-inflammatory interleukin (IL)-10 has been suggested to regulate viral clearance or immunopathology. To determine the role of NKT cells in TMEV-induced myocarditis, we infected wild-type (WT) and NKT knockout (NKT KO, Jα18 KO) mice with TMEV. Myocarditis was monitored by echocardiography using the Vevo 770 system. During the acute (day 7) or chronic phase (day 60) of TMEV infection, cardiac pathology was evaluated by hematoxylin and eosin staining, and production of cytokines, including IFN-γ and IL-10, from spleen cells was measured by enzyme-linked immunosorbent assays. During the acute phase, the levels of left ventricular ejection fraction were significantly lower in NKT KO mice than in WT mice. Immunologically, NKT KO mice had lower levels of IFN-γ production than WT mice [IFN-γ (pg/ml): WT, 768 ± 533; NKT KO, 293 ± 190]. During the chronic phase, high intensity cardiac lesions were observed by echocardiography in NKT KO mice, but not in WT mice. Histologically, NKT KO mice developed moderate inflammation with basophilic degeneration and calcification in the heart, while WT mice had only mild inflammation in the heart. Immunologically, NKT KO mice had lower levels of IL-10 production compared with WT mice [IL-10 (pg/ml): WT, 1771 ± 381; NKT KO, 1199 ± 160]. These results suggest that NKT cells play a protective role in viral myocarditis by producing IFN-γ and IL-10, which contribute to viral clearance during the acute phase and the suppression of immunopathology during the chronic phase of disease, respectively.

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

Clinical Microbiology Reviews ◽

10.1128/cmr.00232-20 ◽

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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Natural Killer Dendritic Cells Enhance Immune Responses Elicited byα-Galactosylceramide-Stimulated Natural Killer T Cells

BioMed Research International ◽

10.1155/2013/460706 ◽

2013 ◽

Vol 2013 ◽

pp. 1-18 ◽

Cited By ~ 3

Author(s):

Sung Won Lee ◽

Hyun Jung Park ◽

Nayoung Kim ◽

Seokmann Hong

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Immune Responses ◽

Natural Killer ◽

Immune Cells ◽

Tumor Antigens ◽

Nkt Cells ◽

Innate Immune ◽

Innate Immune Cells ◽

Natural Killer T

Natural killer dendritic cells (NKDCs) possess potent anti-tumor activity, but the cellular effect of NKDC interactions with other innate immune cells is unclear. In this study, we demonstrate that the interaction of NKDCs and natural killer T (NKT) cells is required for the anti-tumor immune responses that are elicited byα-galactosylceramide (α-GC) in mice. The rapid and strong expression of interferon-γby NKDCs afterα-GC stimulation was dependent on NKT cells. Various NK and DC molecular markers and cytotoxic molecules were up-regulated followingα-GC administration. This up-regulation could improve NKDC presentation of tumor antigens and increase cytotoxicity against tumor cells. NKDCs were required for the stimulation of DCs, NK cells, and NKT cells. The strong anti-tumor immune responses elicited byα-GC may be due to the down-regulation of regulatory T cells. Furthermore, the depletion of NKDCs dampened the tumor clearance mediated byα-GC-stimulated NKT cellsin vivo. Taken together, these results indicate that complex interactions of innate immune cells might be required to achieve optimal anti-tumor immune responses during the early stages of tumorigenesis.

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

Journal of Immunology Research ◽

10.1155/2014/546596 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 6

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.

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Human natural killer T cells acquire a memory-activated phenotype before birth

Blood ◽

10.1182/blood.v95.7.2440 ◽

2000 ◽

Vol 95 (7) ◽

pp. 2440-2442 ◽

Cited By ~ 81

Author(s):

Hans J. J. van der Vliet ◽

Nobusuke Nishi ◽

Tanja D. de Gruijl ◽

B. Mary E. von Blomberg ◽

Alfons J. M. van den Eertwegh ◽

...

Keyword(s):

Autoimmune Diseases ◽

Cord Blood ◽

Natural Killer ◽

Mononuclear Cells ◽

Malignant Tumors ◽

Nkt Cells ◽

Fetal Life ◽

Antitumor Effects ◽

Natural Ligand ◽

Natural Killer T

Abstract Natural killer T (NKT) cells have recently been shown to play an important role in the rejection of malignant tumors and in the regulation of autoimmune diseases. Potent antitumor effects of the marine sponge–derived NKT cell ligand KRN7000 were observed in mice. Therefore, the elucidation of the natural ligand of NKT cells, which is currently still unknown, might have important clinical consequences for the treatment of cancer and autoimmune diseases. Analysis of cord blood mononuclear cells from healthy term infants demonstrated that in sharp contrast with the vast majority of cord blood lymphocytes, human NKT cells have already acquired a memory-activated phenotype before birth. This observation indicates that NKT cells encounter a natural ligand during fetal life and that this ligand is unlikely to be of microbial origin.

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