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Editorial: Role of CD1- and MR1-Restricted T Cells in Immunity and Disease.
Iwabuchi K, Van Kaer L
(2019) Front Immunol 10: 1837
MeSH Terms: Animals, Antigens, CD1, Histocompatibility Antigens Class I, Humans, Minor Histocompatibility Antigens, Mucosal-Associated Invariant T Cells, Natural Killer T-Cells, Receptors, Antigen, T-Cell, T-Lymphocytes
Added March 3, 2020
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9 MeSH Terms
iNKT Cell Activation Exacerbates the Development of Huntington's Disease in R6/2 Transgenic Mice.
Park HJ, Lee SW, Im W, Kim M, Van Kaer L, Hong S
(2019) Mediators Inflamm 2019: 3540974
MeSH Terms: Animals, Brain, Cytokines, Disease Models, Animal, Disease Progression, Galactosylceramides, Genotype, Huntington Disease, Leukocytes, Lymphocyte Activation, Mice, Mice, Knockout, Natural Killer T-Cells
Show Abstract · Added March 26, 2019
Huntington's disease (HD) is an inherited neurodegenerative disorder which is caused by a mutation of the huntingtin (HTT) gene. Although the pathogenesis of HD has been associated with inflammatory responses, if and how the immune system contributes to the onset of HD is largely unknown. Invariant natural killer T (iNKT) cells are a group of innate-like regulatory T lymphocytes that can rapidly produce various cytokines such as IFN and IL4 upon stimulation with the glycolipid -galactosylceramide (-GalCer). By employing both R6/2 Tg mice (murine HD model) and J18 KO mice (deficient in iNKT cells), we investigated whether alterations of iNKT cells affect the development of HD in R6/2 Tg mice. We found that J18 KO R6/2 Tg mice showed disease progression comparable to R6/2 Tg mice, indicating that the absence of iNKT cells did not have any significant effects on HD development. However, repeated activation of iNKT cells with -GalCer facilitated HD progression in R6/2 Tg mice, and this was associated with increased infiltration of iNKT cells in the brain. Taken together, our results demonstrate that repeated -GalCer treatment of R6/2 Tg mice accelerates HD progression, suggesting that immune activation can affect the severity of HD pathogenesis.
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13 MeSH Terms
The Role of Autophagy in iNKT Cell Development.
Yang G, Driver JP, Van Kaer L
(2018) Front Immunol 9: 2653
MeSH Terms: Animals, Autophagy, Cell Differentiation, Humans, Natural Killer T-Cells, Receptors, Antigen, T-Cell, alpha-beta, Thymus Gland
Show Abstract · Added March 26, 2019
CD1d-restricted invariant natural killer T (iNKT) cells are innate-like T cells that express an invariant T cell receptor (TCR) α-chain and recognize self and foreign glycolipid antigens. They can rapidly respond to agonist activation and stimulate an extensive array of immune responses. Thymic development and function of iNKT cells are regulated by many different cellular processes, including autophagy, a self-degradation mechanism. In this mini review, we discuss the current understanding of how autophagy regulates iNKT cell development and effector lineage differentiation. Importantly, we propose that iNKT cell development is tightly controlled by metabolic reprogramming.
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7 MeSH Terms
iNKT Cells Suppress Pathogenic NK1.1CD8 T Cells in DSS-Induced Colitis.
Lee SW, Park HJ, Cheon JH, Wu L, Van Kaer L, Hong S
(2018) Front Immunol 9: 2168
MeSH Terms: Animals, CD8-Positive T-Lymphocytes, Colitis, Dextran Sulfate, Humans, Interferon-gamma, Mice, Mice, Knockout, Natural Killer T-Cells, T-Lymphocytes, Regulatory
Show Abstract · Added March 26, 2019
T cells producing IFNγ play a pathogenic role in the development of inflammatory bowel disease (IBD). To investigate the functions of CD1d-dependent invariant natural killer T (iNKT) cells in experimental colitis induced in Yeti mice with dysregulated expression of IFNγ, we generated iNKT cell-deficient Yeti/CD1d KO mice and compared colitis among WT, CD1d KO, Yeti, and Yeti/CD1d KO mice following DSS treatment. We found that deficiency of iNKT cells exacerbated colitis and disease pathogenesis was mainly mediated by NK1.1CD8 T cells. Furthermore, the protective effects of iNKT cells correlated with up-regulation of regulatory T cells. Taken together, our results have demonstrated that CD1d-dependent iNKT cells and CD1d-independent NK1.1CD8 T cells reciprocally regulate the development of intestinal inflammatory responses mediated by IFNγ-dysregulation. These findings also identify NK1.1CD8 T cells as novel target cells for the development of therapeutics for human IBD.
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10 MeSH Terms
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
Beyond Epstein-Barr virus: genetic predisposition of natural killer T-cell lymphoma.
Reddy NM, Sethi TK
(2016) Lancet Oncol 17: 1176-7
MeSH Terms: Genetic Predisposition to Disease, Herpesvirus 4, Human, Humans, Killer Cells, Natural, Lymphoma, Natural Killer T-Cells
Added August 3, 2016
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6 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
IL-15 Superagonist Expands mCD8+ T, NK and NKT Cells after Burn Injury but Fails to Improve Outcome during Burn Wound Infection.
Patil NK, Luan L, Bohannon JK, Guo Y, Hernandez A, Fensterheim B, Sherwood ER
(2016) PLoS One 11: e0148452
MeSH Terms: Adaptive Immunity, Animals, Burns, CD8-Positive T-Lymphocytes, Cytokines, Disease Models, Animal, Humans, Interleukin-15, Killer Cells, Natural, Liver, Lymphocyte Activation, Lymphocyte Count, Lymphocyte Subsets, Male, Mice, Mice, Inbred BALB C, Natural Killer T-Cells, Pseudomonas Infections, Pseudomonas aeruginosa, Receptors, Interleukin-15, Recombinant Fusion Proteins, Spleen, Wound Infection
Show Abstract · Added February 18, 2016
BACKGROUND - Severely burned patients are highly susceptible to opportunistic infections and sepsis, owing to the loss of the protective skin barrier and immunological dysfunction. Interleukin-15 (IL-15) belongs to the IL-2 family of common gamma chain cytokines and stimulates the proliferation and activation of T (specifically memory CD8), NK and NKT cells. It has been shown to preserve T cell function and improve survival during cecal ligation and puncture (CLP)-induced sepsis in mice. However, the therapeutic efficacy of IL-15 or IL-15 superagonist (SA) during infection after burn injury has not been evaluated. Moreover, very few, if any, studies have examined, in detail, the effect of burn injury and infection on the adaptive immune system. Thus, we examined the effect of burn and sepsis on adaptive immune cell populations and the effect of IL-15 SA treatment on the host response to infection.
METHODS - Mice were subjected to a 35% total body surface area burn, followed by wound infection with Pseudomonas aeruginosa. In some experiments, IL-15 SA was administered after burn injury, but before infection. Leukocytes in spleen, liver and peritoneal cavity were characterized using flow cytometry. Bacterial clearance, organ injury and survival were also assessed.
RESULTS - Burn wound infection led to a significant decline in total white blood cell and lymphocyte counts and induced organ injury and sepsis. Burn injury caused decline in CD4+ and CD8+ T cells in the spleen, which was worsened by infection. IL-15 treatment inhibited this decline and significantly increased cell numbers and activation, as determined by CD69 expression, of CD4+, CD8+, B, NK and NKT cells in the spleen and liver after burn injury. However, IL-15 SA treatment failed to prevent burn wound sepsis-induced loss of CD4+, CD8+, B, NK and NKT cells and failed to improve bacterial clearance and survival.
CONCLUSION - Cutaneous burn injury and infection cause significant adaptive immune dysfunction. IL-15 SA does not augment host resistance to burn wound sepsis in mice despite inducing proliferation and activation of lymphocyte subsets.
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23 MeSH Terms
Border Patrol Gone Awry: Lung NKT Cell Activation by Francisella tularensis Exacerbates Tularemia-Like Disease.
Hill TM, Gilchuk P, Cicek BB, Osina MA, Boyd KL, Durrant DM, Metzger DW, Khanna KM, Joyce S
(2015) PLoS Pathog 11: e1004975
MeSH Terms: Animals, Disease Models, Animal, Flow Cytometry, Fluorescent Antibody Technique, Francisella tularensis, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Confocal, Natural Killer T-Cells, Respiratory Mucosa, Tularemia
Show Abstract · Added October 2, 2015
The respiratory mucosa is a major site for pathogen invasion and, hence, a site requiring constant immune surveillance. The type I, semi-invariant natural killer T (NKT) cells are enriched within the lung vasculature. Despite optimal positioning, the role of NKT cells in respiratory infectious diseases remains poorly understood. Hence, we assessed their function in a murine model of pulmonary tularemia--because tularemia is a sepsis-like proinflammatory disease and NKT cells are known to control the cellular and humoral responses underlying sepsis. Here we show for the first time that respiratory infection with Francisella tularensis live vaccine strain resulted in rapid accumulation of NKT cells within the lung interstitium. Activated NKT cells produced interferon-γ and promoted both local and systemic proinflammatory responses. Consistent with these results, NKT cell-deficient mice showed reduced inflammatory cytokine and chemokine response yet they survived the infection better than their wild type counterparts. Strikingly, NKT cell-deficient mice had increased lymphocytic infiltration in the lungs that organized into tertiary lymphoid structures resembling induced bronchus-associated lymphoid tissue (iBALT) at the peak of infection. Thus, NKT cell activation by F. tularensis infection hampers iBALT formation and promotes a systemic proinflammatory response, which exacerbates severe pulmonary tularemia-like disease in mice.
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13 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