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  • 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: RECEPTOR ; CELLS ; CELL ; KINASE ; SITE ; MOLECULES ; TRANSDUCTION ; ACTIVATION ; COMPLEX ; COMPLEXES ; ANTIGEN ; T-CELL ; T-CELLS ; BINDING ; PHOSPHORYLATION ; signal transduction ; MHC ; SIGNAL-TRANSDUCTION ; DEGRADATION ; IMMUNITY ; LIPID RAFTS ; REVEALS ; NAIVE ; RECEPTORS ; signaling ; monitoring ; TECHNOLOGY ; immunology ; SRC-FAMILY KINASES ; MAINTENANCE ; CD4 RECEPTOR ; IMMUNE ; CATALYTIC-ACTIVITY ; PROTEIN-TYROSINE KINASE
    Abstract: T cell antigen receptor (TCR) and coreceptor ligation is thought to initiate signal transduction by inducing activation of the kinase Lck. Here we showed that catalytically active Lck was present in unstimulated naive T cells and thymocytes and was readily detectable in these cells in lymphoid organs. In naive T cells up to similar to 40% of total Lck was constitutively activated, part of which was also phosphorylated on the C-terminal inhibitory site. Formation of activated Lck was independent of TCR and coreceptors but required Lck catalytic activity and its maintenance relied on monitoring by the HSP90-CDC37 chaperone complex to avoid degradation. The amount of activated Lck did not change after TCR and coreceptor engagement; however it determined the extent of TCR-zeta phosphorylation. Our findings suggest a dynamic regulation of Lck activity that can be promptly utilized to initiate T cell activation and have implications for signaling by other immune receptors
    Type of Publication: Journal article published
    PubMed ID: 20541955
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