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  • CELL  (1)
  • FABRY DISEASE  (1)
  • 1
    Keywords: CELLS ; EXPRESSION ; SURVIVAL ; CELL ; human ; IN-VIVO ; EXPOSURE ; MORTALITY ; MICE ; ACTIVATION ; RESPONSES ; INFECTION ; MECHANISM ; DENDRITIC CELLS ; IMMUNE-RESPONSES ; virus ; NO ; HEALTH ; HUMANS ; antigen presentation ; INDIVIDUALS ; immune response ; IMMUNE-RESPONSE ; INFLAMMATORY RESPONSES ; SUPPRESSOR ; elderly ; USA ; ENGLAND ; EXPANSION ; NATURAL-KILLER ; PUBLIC-HEALTH ; MEDICINE ; IFN-GAMMA PRODUCTION ; outcome ; response ; ALPHA-GALACTOSYLCERAMIDE ; Crosstalk ; INNATE IMMUNE-RESPONSE ; KILLER T-CELLS ; MURINE CYTOMEGALOVIRUS ; Myeloid cell ; myeloid cells ; myeloid-derived suppressor cells ; SUPPRESSOR-CELLS ; TUMOR IMMUNOSURVEILLANCE
    Abstract: infection with influenza A virus (IAV) presents a substantial threat to public health worldwide, with young, elderly, and immunodeficient individuals being particularly susceptible. Inflammatory responses play an important role in the fatal outcome of IAV infection, but the mechanism remains unclear. We demonstrate here that the absence of invariant NKT (iNKT) cells in mice during IAV infection resulted in the expansion of myeloid-derived suppressor cells (MDSCs), which suppressed IAV-specific immune responses through the expression of both arginase and NOS, resulting in high IAV titer and increased mortality. Adoptive transfer of iNKT cells abolished the suppressive activity of MDSCs, restored IAV-specific immune responses, reduced IAV titer, and increased survival rate. The crosstalk between iNKT and MDSCs was CD1d- and CD40-dependent. Furthermore, IAV infection and exposure to TLR agonists relieved the suppressive activity of MDSCs. Finally, we extended these results to humans by demonstrating the presence of myeloid cells with suppressive activity in the PBLs of individuals infected with IAV and showed that their suppressive activity is substantially reduced by iNKT cell activation. These findings identify what we believe to be a novel immunomodulatory role of iNKT cells, which we suggest could be harnessed to abolish the immunosuppressive activity of MDSCs during IAV infection
    Type of Publication: Journal article published
    PubMed ID: 19033672
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  • 2
    Keywords: MICE ; antigen presentation ; IMMUNE-RESPONSE ; GLUCOSYLCERAMIDE SYNTHASE ; ALPHA-CHAIN ; KILLER T-CELLS ; ISOGLOBOTRIHEXOSYLCERAMIDE IGB3 ; STORAGE DISEASES ; CELLULAR LIPIDS ; FABRY DISEASE
    Abstract: Recognition of endogenous lipid Ag(s) on CD1d is required for the development of invariant NKT (iNKT) cells. Isoglobotrihexosylceramide (iGb3) has been implicated as this endogenous selecting ligand and recently suggested to control overstimulation and deletion of iNKT cells in alpha-galactosidase A-deficient (alphaGalA(-/-)) mice (human Fabry disease), which accumulate isoglobosides and globosides. However, the presence and function of iGb3 in murine thymus remained controversial. In this study, we generate a globotrihexosylceramide (Gb3)-synthase-deficient (Gb3S(-/-)) mouse and show that in thymi of alphaGalA(-/-)/Gb3S(-/-) double-knockout mice, which store isoglobosides but no globosides, minute amounts of iGb3 can be detected by HPLC. Furthermore, we demonstrate that iGb3 deficiency does not only fail to impact selection of iNKT cells, in terms of frequency and absolute numbers, but also does not alter the distribution of the TCR CDR 3 of iNKT cells. Analyzing multiple gene-targeted mouse strains, we demonstrate that globoside, rather than iGb3, storage is the major cause for reduced iNKT cell frequencies and defective Ag presentation in alphaGalA(-/-) mice. Finally, we show that correction of globoside storage in alphaGalA(-/-) mice by crossing them with Gb3S(-/-) normalizes iNKT cell frequencies and dendritic cell (DC) function. We conclude that, although detectable in murine thymus in alphaGalA(-/-)/Gb3S(-/-) mice, iGb3 does not influence either the development of iNKT cells or their interaction with peripheral DCs. Moreover, in alphaGalA(-/-) mice, it is the Gb3 storage that is responsible for the decreased iNKT cell numbers and impeded Ag presentation on DCs.
    Type of Publication: Journal article published
    PubMed ID: 22875802
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