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 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.

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 Integrin-mediated Ras–Extracellular Regulated Kinase (ERK) Signaling Regulates Interferon γ Production in Human Natural Killer Cells

1998 ◽  
Vol 188 (7) ◽  
pp. 1267-1275 ◽  
Author(s):  
Fabrizio Mainiero ◽  
Angela Gismondi ◽  
Alessandra Soriani ◽  
Marco Cippitelli ◽  
Gabriella Palmieri ◽  
...  
Keyword(s):  
Natural Killer ◽  
Growth Factor Receptor ◽  
Interferon Γ ◽  
Mitogen Activated Protein Kinase ◽  
Specific Gene ◽  
Β1 Integrin ◽  
Cell Functions ◽  
Tyrosine Kinase 2 ◽  
Β1 Integrins ◽  
Ifn Γ

Recent evidence indicates that integrin engagement results in the activation of biochemical signaling events important for regulating different cell functions, such as migration, adhesion, proliferation, differentiation, apoptosis, and specific gene expression. Here, we report that β1 integrin ligation on human natural killer (NK) cells results in the activation of Ras/mitogen-activated protein kinase pathways. Formation of Shc–growth factor receptor–bound protein 2 (Grb2) and Shc–proline-rich tyrosine kinase 2–Grb2 complexes are the receptor-proximal events accompanying the β1 integrin–mediated Ras activation. In addition, we demonstrate that ligation of β1 integrins results in the stimulation of interferon γ (IFN-γ) production, which is under the control of extracellular signal–regulated kinase 2 activation. Overall, our data indicate that β1 integrins, by delivering signals capable of triggering IFN-γ production, may function as NK-activating receptors.

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

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.

scholarly journals Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications

Blood ◽  
2006 ◽  
Vol 108 (2) ◽  
pp. 618-621 ◽  
Author(s):  
David H. Chang ◽  
Nancy Liu ◽  
Virginia Klimek ◽  
Hani Hassoun ◽  
Amitabha Mazumder ◽  
...  
Keyword(s):  
Natural Killer ◽  
Cell Function ◽  
Nkt Cells ◽  
Interferon Γ ◽  
Therapeutic Implications ◽  
Healthy Donors ◽  
Specific Expansion ◽  
Innate Lymphocytes ◽  
Natural Killer T

Natural killer T (NKT) cells are CD1d-restricted glycolipid reactive innate lymphocytes that play an important role in protection from pathogens and tumors. Pharmacologic approaches to enhance NKT cell function will facilitate specific NKT targeting in the clinic. Here we show that lenalidomide (LEN), a novel thalidomide (Thal) analog, enhances antigen-specific expansion of NKT cells in response to the NKT ligand α-galactosylceramide (α-GalCer) in both healthy donors and patients with myeloma. NKT cells activated in the presence of LEN have greater ability to secrete interferon-γ. Antigen-dependent activation of NKT cells was greater in the presence of dexamethasone (DEX) plus LEN than with DEX alone. Therapy with LEN/Thal also led to an increase in NKT cells in vivo in patients with myeloma and del5q myelodysplastic syndrome. Together these data demonstrate that LEN and its analogues enhance CD1d-mediated presentation of glycolipid antigens and support combining these agents with NKT targeted approaches for protection against tumors.

scholarly journals Sphingosine Kinase Blockade Leads to Increased Natural Killer T Cell Responses to Mantle Cell Lymphoma

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1030 ◽  
Author(s):  
Michael S. Lee ◽  
Wenji Sun ◽  
Tonya J. Webb
Keyword(s):  
Mantle Cell Lymphoma ◽  
Natural Killer ◽  
Cell Lymphoma ◽  
Sphingosine Kinase ◽  
Nkt Cells ◽  
Sphingolipid Metabolism ◽  
Immune Recognition ◽  
Nkt Cell ◽  
Mantle Cell ◽  
Natural Killer T

Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin’s lymphoma. Despite being responsive to combination chemotherapy, median survival remains around 5 years due to high rates of relapse. Sphingolipid metabolism regulates MCL survival and proliferation and we found that sphingosine-1-phosphate (S1P) is upregulated in MCL cells. Therapeutic targeting of the S1P1 receptor or knockdown of sphingosine kinase 1 (SK1), the enzyme responsible for generating S1P, in human MCL cells results in a significant increase in Natural Killer T (NKT) cell activation. NKT cells recognize glycolipid antigens presented on CD1d and can reduce MCL tumor burden in vivo. Lipidomic studies identified cardiolipin, which has been reported to bind to CD1d molecules, as being upregulated in SK1 knockdown cells. We found that the pretreatment of antigen presenting cells with cardiolipin leads to increased cytokine production by NKT cell hybridomas. Furthermore, the ability of cardiolipin to activate NKT cells was dependent on the structure of its acyl chains. Collectively, these studies delineate novel pathways important for immune recognition of malignant cells and could lead to the development of new treatments for lymphoma.

scholarly journals Dysfunction of Natural Killer T Cells in Patients with Active Mycobacterium tuberculosis Infection

2012 ◽  
Vol 80 (6) ◽  
pp. 2100-2108 ◽  
Author(s):  
Seung-Jung Kee ◽  
Yong-Soo Kwon ◽  
Yong-Wook Park ◽  
Young-Nan Cho ◽  
Sung-Ji Lee ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Natural Killer ◽  
Extrapulmonary Tuberculosis ◽  
Poor Response ◽  
Nkt Cells ◽  
Tuberculosis Infection ◽  
Nkt Cell ◽  
Content Type ◽  
The Poor ◽  
Natural Killer T

ABSTRACTNatural killer T (NKT) cells are known to play a protective role in the immune responses of mice against a variety of infectious pathogens. However, little is known about the detailed information of NKT cells in patients withMycobacterium tuberculosisinfection. The aims of this study were to examine NKT cell levels and functions in patients with activeM. tuberculosisinfection, to investigate relationships between NKT cell levels and clinical parameters, and to determine the mechanism responsible for the poor response to α-galactosylceramide (α-GalCer). NKT cell levels were significantly lower in the peripheral blood of pulmonary tuberculosis and extrapulmonary tuberculosis patients, and the proliferative responses of NKT cells to α-GalCer were also lower in patients, whereas NKT cell levels and responses were comparable in latent tuberculosis infection subjects and healthy controls. Furthermore, this NKT cell deficiency was found to be correlated with serum C-reactive protein levels. In addition, the poor response to α-GalCer inM. tuberculosis-infected patients was found to be due to increased NKT cell apoptosis, reduced CD1d expression, and a defect in NKT cells. Notably,M. tuberculosisinfection was associated with an elevated expression of the inhibitory programmed death-1 (PD-1) receptor on NKT cells, and blockade of PD-1 signaling enhanced the response to α-GalCer. This study shows that NKT cell levels and functions are reduced inM. tuberculosis-infected patients and these deficiencies were found to reflect the presence of active tuberculosis.

scholarly journals A Natural Killer T (NKT) Cell Developmental Pathway Involving a Thymus-dependent NK1.1−CD4+ CD1d-dependent Precursor Stage

2002 ◽  
Vol 195 (7) ◽  
pp. 835-844 ◽  
Author(s):  
Daniel G. Pellicci ◽  
Kirsten J.L. Hammond ◽  
Adam P. Uldrich ◽  
Alan G. Baxter ◽  
Mark J. Smyth ◽  
...  
Keyword(s):  
Natural Killer ◽  
Nkt Cells ◽  
Developmental Pathway ◽  
Nkt Cell ◽  
Tetramer Binding ◽  
Development In Vitro ◽  
A Minor ◽  
Natural Killer T

The development of CD1d-dependent natural killer T (NKT) cells is poorly understood. We have used both CD1d/α-galactosylceramide (CD1d/αGC) tetramers and anti-NK1.1 to investigate NKT cell development in vitro and in vivo. Confirming the thymus-dependence of these cells, we show that CD1d/αGC tetramer-binding NKT cells, including NK1.1+ and NK1.1− subsets, develop in fetal thymus organ culture (FTOC) and are completely absent in nude mice. Ontogenically, CD1d/αGC tetramer-binding NKT cells first appear in the thymus, at day 5 after birth, as CD4+CD8−NK1.1−cells. NK1.1+ NKT cells, including CD4+ and CD4−CD8− subsets, appeared at days 7–8 but remained a minor subset until at least 3 wk of age. Using intrathymic transfer experiments, CD4+NK1.1− NKT cells gave rise to NK1.1+ NKT cells (including CD4+ and CD4− subsets), but not vice-versa. This maturation step was not required for NKT cells to migrate to other tissues, as NK1.1− NKT cells were detected in liver and spleen as early as day 8 after birth, and the majority of NKT cells among recent thymic emigrants (RTE) were NK1.1−. Further elucidation of this NKT cell developmental pathway should prove to be invaluable for studying the mechanisms that regulate the development of these cells.

scholarly journals Frequency and Phenotype of Circulating Vα24/Vβ11 Double-Positive Natural Killer T Cells during Hepatitis C Virus Infection

2003 ◽  
Vol 77 (3) ◽  
pp. 2251-2257 ◽  
Author(s):  
Michaela Lucas ◽  
Stephan Gadola ◽  
Ute Meier ◽  
Neil T. Young ◽  
Gillian Harcourt ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Natural Killer ◽  
Natural Killer T Cells ◽  
Nkt Cells ◽  
Hepatitis C Virus Infection ◽  
Double Positive ◽  
Nkt Cell ◽  
Killer T Cells ◽  
Natural Killer T

ABSTRACT Natural killer T (NKT) cells are thought to be involved in innate responses against infection. We investigated one specific type of NKT cell, Vα24/Vβ11 double positive, in hepatitis C virus (HCV) infection. Lower frequencies of this population were detected in the blood of HCV PCR-positive patients than in controls. Unlike Vα24/Vβ11 NKT cells found in blood, those in the liver appeared to be recently activated.

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