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Graphene oxide polarizes iNKT cells for production of TGFβ and attenuates inflammation in an iNKT cell-mediated sepsis model.
Lee SW, Park HJ, Van Kaer L, Hong S, Hong S
(2018) Sci Rep 8: 10081
MeSH Terms: Animals, Antigens, CD1d, Cell Polarity, Dendritic Cells, Disease Models, Animal, Galactosylceramides, Graphite, Humans, Inflammation, Intraepithelial Lymphocytes, Lymphocyte Activation, Mice, Nanotubes, Carbon, Natural Killer T-Cells, Sepsis, Toll-Like Receptor 4, Transforming Growth Factor beta
Show Abstract · Added March 26, 2019
Graphene oxide (GO) modulates the functions of antigen-presenting cells including dendritic cells (DCs). Although carbon nanotubes affect expression of the MHC class I-like CD1d molecule, whether GO can influence immune responses of CD1d-dependent invariant natural killer T (iNKT) cells remains unclear. Here, we investigated the impact of GO on inflammatory responses mediated by α-galactosylceramide (α-GalCer), an iNKT cell agonist. We found that in vivo GO treatment substantially inhibited the capacity of α-GalCer to induce the iNKT cell-mediated trans-activation of and cytokine production by innate and innate-like cells, including DCs, macrophages, NK cells, and γδ T cells. Such effects of GO on α-GalCer-induced inflammatory responses closely correlated with iNKT cell polarization towards TGFβ production, which also explains the capacity of GO to expand regulatory T cells. Interestingly, the absence of TLR4, a receptor for GO, failed to downregulate, and instead partially enhanced the anti-inflammatory activity of GO against α-GalCer-elicited responses, implying negative effects of TLR4 signaling on the anti-inflammatory properties of GO. By employing an α-GalCer-induced sepsis model, we further demonstrated that GO treatment significantly protected mice from α-GalCer-induced lethality. Taken together, we provide strong evidence that GO holds promise as an adjuvant to modulate iNKT cell responses for immunotherapy.
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17 MeSH Terms
Adipocyte-specific CD1d-deficiency mitigates diet-induced obesity and insulin resistance in mice.
Satoh M, Hoshino M, Fujita K, Iizuka M, Fujii S, Clingan CS, Van Kaer L, Iwabuchi K
(2016) Sci Rep 6: 28473
MeSH Terms: 3T3-L1 Cells, Adipocytes, Adiponectin, Animals, Antigen Presentation, Antigens, CD1d, B7-1 Antigen, Diet, High-Fat, Disease Models, Animal, Disease Progression, Galactosylceramides, Insulin Resistance, Interferon-gamma, Lymphocyte Activation, Macrophage Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Natural Killer T-Cells, Obesity
Show Abstract · Added July 30, 2016
It has been shown that CD1d expression and glycolipid-reactive, CD1d-restricted NKT cells exacerbate the development of obesity and insulin resistance in mice. However, the relevant CD1d-expressing cells that influence the effects of NKT cells on the progression of obesity remain incompletely defined. In this study, we have demonstrated that 3T3-L1 adipocytes can present endogenous ligands to NKT cells, leading to IFN-γ production, which in turn, stimulated 3T3-L1 adipocytes to enhance expression of CD1d and CCL2, and decrease expression of adiponectin. Furthermore, adipocyte-specific CD1d deletion decreased the size of the visceral adipose tissue mass and enhanced insulin sensitivity in mice fed a high-fat diet (HFD). Accordingly, NKT cells were less activated, IFN-γ production was significantly reduced, and levels of adiponectin were increased in these animals as compared with control mice on HFD. Importantly, macrophage recruitment into the adipose tissue of adipocyte-specific CD1d-deficient mice was significantly blunted. These findings indicate that interactions between NKT cells and CD1d-expressing adipocytes producing endogenous NKT cell ligands play a critical role in the induction of inflammation and functional modulation of adipose tissue that leads to obesity.
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21 MeSH Terms
Natural killer T cells in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis.
Van Kaer L, Wu L, Parekh VV
(2015) Immunology 146: 1-10
MeSH Terms: Animals, Antigens, CD1d, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Galactosylceramides, Humans, Immunotherapy, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Multiple Sclerosis, Natural Killer T-Cells
Show Abstract · Added September 28, 2015
Multiple sclerosis (MS) is a chronic inflammatory disease that causes demyelination of neurons in the central nervous system. Traditional therapies for MS have involved anti-inflammatory and immunosuppressive drugs with significant side effects that often only provide short-term relief. A more desirable outcome of immunotherapy would be to protect against disease before its clinical manifestation or to halt disease after its initiation. One attractive approach to accomplish this goal would be to restore tolerance by targeting immunoregulatory cell networks. Although much of the work in this area has focused on CD4(+) Foxp3(+) regulatory T cells, other studies have investigated natural killer T (NKT) cells, a subset of T cells that recognizes glycolipid antigens in the context of the CD1d glycoprotein. Studies with human MS patients have revealed alterations in the numbers and functions of NKT cells, which have been partially supported by studies with the experimental autoimmune encephalomyelitis model of MS. Additional studies have shown that activation of NKT cells with synthetic lipid antigens can, at least under certain experimental conditions, protect mice against the development of MS-like disease. Although mechanisms of this protection remain to be fully investigated, current evidence suggests that it involves interactions with other immunoregulatory cell types such as regulatory T cells and immunosuppressive myeloid cells. These studies have provided a strong foundation for the rational design of NKT-cell-based immunotherapies for MS that induce tolerance while sparing overall immune function. Nevertheless, additional pre-clinical and clinical studies will be required to bring this goal to fruition.
© 2015 John Wiley & Sons Ltd.
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12 MeSH Terms
Specific deletion of LDL receptor-related protein on macrophages has skewed in vivo effects on cytokine production by invariant natural killer T cells.
Covarrubias R, Wilhelm AJ, Major AS
(2014) PLoS One 9: e102236
MeSH Terms: Adaptive Immunity, Animals, Antigens, CD1d, B-Lymphocytes, Cells, Cultured, Cytokines, Dendritic Cells, Gene Knockout Techniques, Immunoglobulin E, Low Density Lipoprotein Receptor-Related Protein-1, Lymphocyte Activation, Macrophages, Mice, Inbred C57BL, Mice, Knockout, Natural Killer T-Cells, Receptors, LDL, Tumor Suppressor Proteins
Show Abstract · Added January 20, 2015
Expression of molecules involved in lipid homeostasis such as the low density lipoprotein receptor (LDLr) on antigen presenting cells (APCs) has been shown to enhance invariant natural killer T (iNKT) cell function. However, the contribution to iNKT cell activation by other lipoprotein receptors with shared structural and ligand binding properties to the LDLr has not been described. In this study, we investigated whether a structurally related receptor to the LDLr, known as LDL receptor-related protein (LRP), plays a role in iNKT cell activation. We found that, unlike the LDLr which is highly expressed on all immune cells, the LRP was preferentially expressed at high levels on F4/80+ macrophages (MΦ). We also show that CD169+ MΦs, known to present antigen to iNKT cells, exhibited increased expression of LRP compared to CD169- MΦs. To test the contribution of MΦ LRP to iNKT cell activation we used a mouse model of MΦ LRP conditional knockout (LRP-cKO). LRP-cKO MΦs pulsed with glycolipid alpha-galactosylceramide (αGC) elicited normal IL-2 secretion by iNKT hybridoma and in vivo challenge of LRP-cKO mice led to normal IFN-γ, but blunted IL-4 response in both serum and intracellular expression by iNKT cells. Flow cytometric analyses show similar levels of MHC class-I like molecule CD1d on LRP-cKO MΦs and normal glycolipid uptake. Survey of the iNKT cell compartment in LRP-cKO mice revealed intact numbers and percentages and no homeostatic disruption as evidenced by the absence of programmed death-1 and Ly-49 surface receptors. Mixed bone marrow chimeras showed that the inability iNKT cells to make IL-4 is cell extrinsic and can be rescued in the presence of wild type APCs. Collectively, these data demonstrate that, although MΦ LRP may not be necessary for IFN-γ responses, it can contribute to iNKT cell activation by enhancing early IL-4 secretion.
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17 MeSH Terms
Molecular signatures mostly associated with NK cells are predictive of relapse free survival in breast cancer patients.
Ascierto ML, Idowu MO, Zhao Y, Khalak H, Payne KK, Wang XY, Dumur CI, Bedognetti D, Tomei S, Ascierto PA, Shanker A, Bear HD, Wang E, Marincola FM, De Maria A, Manjili MH
(2013) J Transl Med 11: 145
MeSH Terms: Antigens, CD1d, Breast Neoplasms, Cell Adhesion Molecules, Cell Count, Disease-Free Survival, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Killer Cells, Natural, Lymphocyte Activation, Lymphocyte Function-Associated Antigen-1, Neoplasm Recurrence, Local, Recurrence, Signal Transduction, Support Vector Machine, Treatment Outcome
Show Abstract · Added March 7, 2014
BACKGROUND - Recent observations suggest that immune-mediated tissue destruction is dependent upon coordinate activation of immune genes expressed by cells of the innate and adaptive immune systems.
METHODS - Here, we performed a retrospective pilot study to investigate whether the coordinate expression of molecular signature mostly associated with NK cells could be used to segregate breast cancer patients into relapse and relapse-free outcomes.
RESULTS - By analyzing primary breast cancer specimens derived from patients who experienced either 58-116 months (~5-9 years) relapse-free survival or developed tumor relapse within 9-76 months (~1-6 years) we found that the expression of molecules involved in activating signaling of NK cells and in NK cells: target interaction is increased in patients with favorable prognosis.
CONCLUSIONS - The parameters identified in this study, together with the prognostic signature previously reported by our group, highlight the cooperation between the innate and adaptive immune components within the tumor microenvironment.
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17 MeSH Terms
Invariant natural killer T cells as sensors and managers of inflammation.
Van Kaer L, Parekh VV, Wu L
(2013) Trends Immunol 34: 50-8
MeSH Terms: Animals, Antigens, CD1d, Humans, Immunotherapy, Infections, Inflammation, Lymphocyte Activation, Mice, Natural Killer T-Cells
Show Abstract · Added March 7, 2014
Invariant natural killer T (iNKT) cells are a subset of innate-like lymphocytes that recognize glycolipid antigens bound by the major histocompatibility complex (MHC)-class-I-related protein CD1d. iNKT cells are activated early during a variety of infections and inflammatory diseases and contribute to the subsequent development of adaptive immune responses. Consequently, iNKT cells play a critical role in the development and resolution of inflammatory diseases and represent attractive targets for the development of immunotherapies. Recent studies have provided important insight into the mechanisms by which iNKT cells become activated in response to diverse inflammatory stimuli. These new findings should be instrumental to promote the immunomodulatory properties of iNKT cells for treatment of inflammatory diseases.
Copyright © 2012 Elsevier Ltd. All rights reserved.
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2 Members
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9 MeSH Terms
Natural killer T cells are required for lipopolysaccharide-mediated enhancement of atherosclerosis in apolipoprotein E-deficient mice.
Andoh Y, Ogura H, Satoh M, Shimano K, Okuno H, Fujii S, Ishimori N, Eshima K, Tamauchi H, Otani T, Nakai Y, Van Kaer L, Tsutsui H, Onoé K, Iwabuchi K
(2013) Immunobiology 218: 561-9
MeSH Terms: Animals, Antigens, CD1d, Apolipoproteins E, Atherosclerosis, Lipopolysaccharides, Lymphocyte Activation, Mice, Mice, Knockout, Natural Killer T-Cells
Show Abstract · Added March 20, 2014
Lipopolysaccharide (LPS) has been shown to accelerate atherosclerosis and to increase the prevalence of IL-4-producing natural killer T (NKT) cells in various tissues. However, the role of NKT cells in the development of LPS-induced atherosclerotic lesions has not been fully tested in NKT cell-deficient mice. Here, we examined the lesion development in apolipoprotein E knockout (apoE-KO) mice and apoE-KO mice on an NKT cell-deficient, CD1d knockout (CD1d-KO) background (apoE-CD1d double knockout; DKO). LPS (0.5 μg/g body weight/wk) or phosphate-buffered saline (PBS) was intraperitoneally administered to apoE-KO and DKO mice (8-wk old) for 5 wk and atherosclerotic lesion areas were quantified thereafter. Consistent with prior reports, NKT cell-deficient DKO mice showed milder atherosclerotic lesions than apoE-KO mice. Notably, LPS administration significantly increased the lesion size in apoE-KO, but not in DKO mice, compared to PBS controls. Our findings suggest that LPS, and possibly LPS-producing bacteria, aggravate the development of atherosclerosis primarily through NKT cell activation and subsequent collaboration with NK cells.
Copyright © 2012 Elsevier GmbH. All rights reserved.
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9 MeSH Terms
Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice.
Wu L, Parekh VV, Gabriel CL, Bracy DP, Marks-Shulman PA, Tamboli RA, Kim S, Mendez-Fernandez YV, Besra GS, Lomenick JP, Williams B, Wasserman DH, Van Kaer L
(2012) Proc Natl Acad Sci U S A 109: E1143-52
MeSH Terms: Adipose Tissue, White, Animals, Antigens, CD1d, CD8-Positive T-Lymphocytes, Cells, Cultured, Cytokines, Dietary Fats, Fatty Liver, Female, Flow Cytometry, Galactosylceramides, Inflammation, Inflammation Mediators, Insulin Resistance, Lipids, Lymphocyte Activation, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Natural Killer T-Cells, Obesity
Show Abstract · Added March 4, 2013
Obesity triggers a low-grade systemic inflammation, which plays an important role in the development of obesity-associated metabolic diseases. In searching for links between lipid accumulation and chronic inflammation, we examined invariant natural killer T (iNKT) cells, a subset of T lymphocytes that react with lipids and regulate inflammatory responses. We show that iNKT cells respond to dietary lipid excess and become activated before or at the time of tissue recruitment of inflammatory leukocytes, and that these cells progressively increase proinflammatory cytokine production in obese mice. Such iNKT cells skew other leukocytes toward proinflammatory cytokine production and induce an imbalanced proinflammatory cytokine environment in multiple tissues. Further, iNKT cell deficiency ameliorates tissue inflammation and provides protection against obesity-induced insulin resistance and hepatic steatosis. Conversely, chronic iNKT cell stimulation using a canonical iNKT cell agonist exacerbates tissue inflammation and obesity-associated metabolic disease. These findings place iNKT cells into the complex network linking lipid excess to inflammation in obesity and suggest new therapeutic avenues for obesity-associated metabolic disorders.
1 Communities
4 Members
0 Resources
23 MeSH Terms
Adaptability of the semi-invariant natural killer T-cell receptor towards structurally diverse CD1d-restricted ligands.
Florence WC, Xia C, Gordy LE, Chen W, Zhang Y, Scott-Browne J, Kinjo Y, Yu KO, Keshipeddy S, Pellicci DG, Patel O, Kjer-Nielsen L, McCluskey J, Godfrey DI, Rossjohn J, Richardson SK, Porcelli SA, Howell AR, Hayakawa K, Gapin L, Zajonc DM, Wang PG, Joyce S
(2009) EMBO J 28: 3579-90
MeSH Terms: Adaptation, Biological, Animals, Antigen Presentation, Antigens, CD1d, Antigens, Tumor-Associated, Carbohydrate, Cells, Cultured, Galactosylceramides, Ligands, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Models, Molecular, Natural Killer T-Cells, Receptors, Antigen, T-Cell, Receptors, Antigen, T-Cell, alpha-beta, Structure-Activity Relationship, T-Cell Antigen Receptor Specificity
Show Abstract · Added May 19, 2014
The semi-invariant natural killer (NK) T-cell receptor (NKTcr) recognises structurally diverse glycolipid antigens presented by the monomorphic CD1d molecule. While the alpha-chain of the NKTcr is invariant, the beta-chain is more diverse, but how this diversity enables the NKTcr to recognise diverse antigens, such as an alpha-linked monosaccharide (alpha-galactosylceramide and alpha-galactosyldiacylglycerol) and the beta-linked trisaccharide (isoglobotriaosylceramide), is unclear. We demonstrate here that NKTcrs, which varied in their beta-chain usage, recognised diverse glycolipid antigens with a similar binding mode on CD1d. Nevertheless, the NKTcrs recognised distinct epitopic sites within these antigens, including alpha-galactosylceramide, the structurally similar alpha-galactosyldiacylglycerol and the very distinct isoglobotriaosylceramide. We also show that the relative roles of the CDR loops within the NKTcr beta-chain varied as a function of the antigen. Thus, while NKTcrs characteristically use a conserved docking mode, the NKTcr beta-chain allows these cells to recognise unique aspects of structurally diverse CD1d-restricted ligands.
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17 MeSH Terms
Invariant natural killer T cells: innate-like T cells with potent immunomodulatory activities.
Wu L, Gabriel CL, Parekh VV, Van Kaer L
(2009) Tissue Antigens 73: 535-45
MeSH Terms: Animals, Antigen-Presenting Cells, Antigens, CD1d, Galactosylceramides, Glycolipids, Humans, Immunity, Innate, Immunotherapy, Lymphocyte Activation, Mice, Natural Killer T-Cells, Signal Transduction, T-Lymphocyte Subsets
Show Abstract · Added December 10, 2013
Invariant natural killer T (iNKT) cells are a subset of T lymphocytes that react with glycolipid antigens presented by the major histocompatibility complex class I-related glycoprotein CD1d. Although iNKT cells express an antigen-specific receptor of the adaptive immune system, they behave more like cells of the innate immune system. A hallmark of iNKT cells is their capacity to produce copious amounts of immunoregulatory cytokines quickly after activation. The cytokines produced by iNKT cells can influence the level of activation of many cell types of the innate and adaptive immune systems as well as the quality of an adaptive immune response. As such, iNKT cells have emerged as important regulators of immune responses, playing a role in microbial immunity, autoimmunity, tumor immunity, and a variety of inflammatory conditions. Although several endogenous and exogenous glycolipid antigens of iNKT cells have been identified, how these glycolipids orchestrate iNKT-cell functions remains poorly understood. Nevertheless, iNKT cells hold substantial promise as targets for development of vaccine adjuvants and immunotherapies. These properties of iNKT cells have been investigated most extensively in mouse models of human disease using the marine sponge-derived agent alpha-galactosylceramide (alpha-GalCer) and related iNKT-cell antigens. While these preclinical studies have raised enthusiasm for developing iNKT-cell-based immunotherapies, they also showed potential health risks associated with iNKT cell activation. Although alpha-GalCer treatment in humans was shown to be safe in the short term, further studies are needed to develop safe and effective iNKT-cell-based therapies.
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13 MeSH Terms