| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
The phenotypic and functional changes of glycolipid/CD1d-reactive Vαl4^+ T cells in the liver of mice during bacterial infection were investigated. After Listeria monocytogenes infection or IL-12 treatment, α-galactosylceramide/CD1d tetramer-reactive (α-GalCer/CD1d^+) T cells coexpressing NK1.1 marker became undetectable and concomitantly cells lacking NK1.1 emerged in both euthymic and thymectomized animals at early stages of infection. Depletion of the NK1.1 subpopulation prevented the emergence of α-GalCer/CD1d^+ NK1.1^- T cells. Before infection, NK1.1^+, rather than NK1.1^-, α-GalCer/CD1d^+ T cells coexpressing CD4 were responsible for IL-4 production, whereas IFN-γ was produced by cells regardless of NK1.1 or CD4 expression. After infection, IL-A-secreting cells became undetectable among α-GalCer/CD1d^+ T cells, but considerable numbers of IFN-γ-secreting cells were found among NK1.1, but not NK1.1^+, cells lacking CD4. Thus, NK1.1 surface expression and functional activities of
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Vαl4^+ T cells underwent dramatic changes at early stages of listeriosis and these alterations progressed in a thymus-independent manner. In mutant mice lacking all α-GalCer/CD1d~^+T cells, listeriosis was ameliorated, suggesting that subtle contribution of the NK1.1^-T-cell subset to antibacterial protection is covered by more profound detrimental effects of the NK1.1^+T-cell subset. At later time points, the NK1.1^- iNKT cell population contracted, whereas NK1.1^+ iNKT cells reemerged. Alterations in NK1.1 surface expression of iNKT cells were paralleled by numerical changes of IL-12 producers in the liver and were completely prevented by endogenous IL-12 neutralization, whereas NK1.1 surface alterations on iNKT cells following α-GalCer stimulation were not prevented. Adoptive cell transfer experiments revealed that the liver NK1.1^- iNKT cells from L.monocytogenes-infected mice accumulated in the liver of recipient recombination-activating gene-1-deficient mice where they acquired NK1.1 surface expression, suggesting that NK1.1 surface expression on liver iNKT cells is reversible during L.monocytogenes infection, and that different mechanisms underlie stimulation by TCR and IL-12. Bacterial growth and inflammation in the liver and spleen following Listeria monocytogenes infection were dramatically inhibited by α-GalCer treatment. Liver infiltration of granulocytes and γ/δ T cells was accelerated by α-GalCer treatment, and depletion of these cells exacerbated listeriosis. Our results indicate that α-GalCer induces antibacterial immunity caused, in part, by accelerated infiltration of inflammatory cells into the liver. Less
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