Glycolipid activation of invariant T cell receptor
            <sup>+</sup>
            NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4
            <sup>+</sup>
            T cells

Meyer, Everett; Goya, Sho; Akbari, Omid; Berry, Gerald J.; Savage, Paul B.; Kronenberg, Mitchell; Nakayama, Toshinori; DeKruyff, Rosemarie H.; Umetsu, Dale T.

doi:10.1073/pnas.0510282103

Cited by 201 publications

(190 citation statements)

References 43 publications

(62 reference statements)

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“…NKT cells were implicated as contributing to the pathogenesis of asthma through their production of IL-13 and IL-4 in mice and were necessary despite the ability of mice deficient in NKT cells to still make a Th2 response (74). Indeed, the stimulation of invariant NKT cells with ␣GalCer or another lipid was sufficient to induce airway hypersensitivity in class II MHC-deficient mice, which lack conventional CD4 ϩ T cells (75). Similarly, NKT cells appeared to be a major source of IL-13 and IL-4 in the lungs of human bronchial asthma patients because CD1d tetramer-binding T cells represented 60% of the CD3 ϩ CD4 ϩ T cells in the lungs of patients with moderate to severe asthma, expressed the invariant TCR, and made Th2 cytokines (76), although this has not been observed in all asthmatics (77).…”

Section: Regulatory Role Of Type I Nkt Cells In Autoimmunity Andmentioning

confidence: 99%

NKT Cells in Tumor Immunity: Opposing Subsets Define a New Immunoregulatory Axis

Berzofsky

Terabe

2008

The Journal of Immunology

108

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Section: Regulatory Role Of Type I Nkt Cells In Autoimmunity Andmentioning

confidence: 99%

NKT Cells in Tumor Immunity: Opposing Subsets Define a New Immunoregulatory Axis

Berzofsky

Terabe

2008

The Journal of Immunology

108

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“…A single dose of 20 ng of ␣-C-GalCer was sufficient to set into motion the many innate and adaptive responses that we measured. A recent study evaluated intranasal injection of ␣-GalCer, which activated pulmonary IL-4-producing NKT cells along with the development of airway hyperreactivity (26,27). To induce antigen-specific T cell immunity with ␣-GalCer through the oral route, Silk et al (8) gave 8 g of ␣-GalCer together with OVA antigen.…”

Section: Cellsmentioning

confidence: 99%

Glycolipid α-C-galactosylceramide is a distinct inducer of dendritic cell function during innate and adaptive immune responses of mice

Fujii

Shimizu

Hemmi

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

154

151

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␣-Galactosylceramide (␣-GalCer) is the prototype compound for studying the presentation of glycolipids on CD1d molecules to natural killer T (NKT) lymphocytes. A single i.v. dose of glycolipid triggers a cascade of events involving the production of several cytokines over the course of a day, a short-lived activation of NKT and natural killer (NK) cells, and a more prolonged adaptive T cell immune response if certain antigens are given together with ␣-GalCer. We find that a recently described analogue, ␣-C-galactosylceramide (␣-C-GalCer), more potently induces these innate and adaptive immune responses in mice. ␣-C-GalCer acts as a more effective trigger for IL-12 and IFN-␥ production, although it minimally elicits IL-4 and TNF-␣ release into the serum. Also, ␣-C-GalCer better mobilizes NKT and natural killer cells to resist B16 melanoma. To help understand these effects, we find that ␣-C-GalCer binds more stably to dendritic cells than ␣-GalCer and that dendritic cells loaded with ␣-C-GalCer induce larger and more long lasting NKT cell responses in vivo. When glycolipid is targeted to dendritic cells in spleen together with antigens in dying cells, such as irradiated tumor cells, ␣-C-GalCer is active as an adjuvant for T cell-mediated immunity at lower doses, just 20 ng per mouse, where it is also able to up-regulate the required CD40L costimulatory molecule on NKT cells. Therefore, ␣-C-GalCer represents a glycolipid that binds more stably to dendritic cells and acts as a more effective link between innate and adaptive immunity in vivo.immune therapy ͉ maturation ͉ natural killer T ͉ CD40L

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“…The requirement for iNKT cells was specific, since adoptive transfer of iNKT cells from wildtype (WT) mice reconstituted the development of AHR in iNKT cell-deficient J␣18 Ϫ/Ϫ mice. These studies of iNKT cells in mice and nonhuman primates (1)(2)(3)(4)(5)(6)(7)(8) strongly suggest that iNKT cells play an important role in human asthma. Indeed, a significant number of CD4…”

mentioning

confidence: 97%

ICOS/ICOSL Interaction Is Required for CD4+ Invariant NKT Cell Function and Homeostatic Survival

Akbari

Stock

Meyer

et al. 2008

The Journal of Immunology

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The development of airway hyperreactivity (AHR), a cardinal feature of asthma, requires the presence of invariant NKT (iNKT) cells. In a mouse model of asthma, we demonstrated that the induction of AHR required ICOS costimulation of iNKT cells. ICOS was highly expressed on both naive and activated iNKT cells, and expression of ICOS was greater on the CD4+ iNKT than on CD4− iNKT cells. Furthermore, the number of CD4+ iNKT cells was significantly lower in spleens and livers of ICOS−/− and ICOSL−/− mice, and the remaining iNKT cells in ICOS−/− mice were dysfunctional and failed to reconstitute AHR when adoptively transferred into iNKT cell-deficient Jα18−/− mice. In addition, direct activation of iNKT cells with α-GalCer, which induced AHR in wild-type mice, failed to induce AHR in ICOS−/− mice. The failure of ICOS−/− iNKT cells to induce AHR was due in part to an inability of the ICOS−/− iNKT cells to produce IL-4 and IL-13 on activation. Moreover, survival of wild-type iNKT cells transferred into ICOSL−/− mice was greatly reduced due to the induction of apoptosis. These results indicate that ICOS costimulation plays a major role in induction of AHR by iNKT cells and is required for CD4+ iNKT cell function, homeostasis, and survival in the periphery.

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Glycolipid activation of invariant T cell receptor ⁺ NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4 ⁺ T cells

Abstract: Asthma is an inflammatory lung disease, in which conventional

Cited by 201 publications

References 43 publications

NKT Cells in Tumor Immunity: Opposing Subsets Define a New Immunoregulatory Axis

NKT Cells in Tumor Immunity: Opposing Subsets Define a New Immunoregulatory Axis

Glycolipid α-C-galactosylceramide is a distinct inducer of dendritic cell function during innate and adaptive immune responses of mice

ICOS/ICOSL Interaction Is Required for CD4+ Invariant NKT Cell Function and Homeostatic Survival

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Glycolipid activation of invariant T cell receptor + NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4 + T cells

Abstract: Asthma is an inflammatory lung disease, in which conventional

Cited by 201 publications

References 43 publications

NKT Cells in Tumor Immunity: Opposing Subsets Define a New Immunoregulatory Axis

NKT Cells in Tumor Immunity: Opposing Subsets Define a New Immunoregulatory Axis

Glycolipid α-C-galactosylceramide is a distinct inducer of dendritic cell function during innate and adaptive immune responses of mice

ICOS/ICOSL Interaction Is Required for CD4+ Invariant NKT Cell Function and Homeostatic Survival

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Glycolipid activation of invariant T cell receptor ⁺ NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4 ⁺ T cells