| Budget Amount *help |
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥5,800,000 (Direct Cost: ¥5,800,000)
Fiscal Year 2002: ¥7,700,000 (Direct Cost: ¥7,700,000)
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| Research Abstract |
Toll-like receptors (TLRs) for bacterial constitutes, are expressed not only by phagocytes but also by some subsets of T cells. We have found that epithelial γδ T cells bearing Vδ1 and intrahepatic NKT cells bearing Vα14 expressed TLRs and play an important role in protection and pathogenesis of liver injury during bacterial infection. as follows.
1 Epithelial γδ T cells bearing Yδ1
An influx of neutrophils followed a short time later by an influx of macrophages to the infected site plays a key role in innate immunity against Eschelichia coli infection. We found that Vδ1^<-/-> mice exhibited impaired accumulation of peritoneal macrophages but not neutrophils and delayed bacterial clearance after intraperitoneal inoculation with E.coli. Peritoneal γδ T cells from E.coli-infected wild-type mice produced CCL3/MIP-la and CCL5/RANTES in response to γδ TCR triggering in vitro, while such production was not evident in γδ T cells from E.coli-infected γδ1^<-/-> mice. Neutralization of CCL3/MIP-la
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by a specific monoclonal antibody in vivo significantly inhibited the accumulation of macrophages in the peritoneal cavity after E.coli infection, resulting in exacerbated bacterial growth in the peritoneal cavity. These results suggest that Vδ1^+γδ T cells bridge a gap between neutrophis and macrophages in innate immunity during E.coli infection mediated by production of CC chemokines, enhancing macrophage trafficking to the site of infection.
2 Intrahepatic NKT cells
Fas ligand (Fas L) expression was induced on intraheaptic NK1.1^+ T cells in vivo after an intraperitoneal inoculation of Escherichia coli. Liver injury after E.coli infection, as assessed by serum GPT level and histological examination, was significantly reduced in Ja281^<-/-> mice lacking NK1.1^+ T cells or in gld/gld mice bearing mutated Fas L, indicating that NK T cells at least partly contribute to E.coli-induced liver injury in a Fas/Fas L-dependent manner. Bacterial numbers in organs and cytokine levels in serum of Ja281^<-/-> mice did not differ from those of Ja281^<+/+> mice following E.coli infection. Intrahepatic NK1.1^+ T cells, which preferentially expressed TLR2mRNA, responded in vitro to synthetic lipoprotein, a ligand for TLR2, by inducing Fas L expression on their surface. In a manner analogous to E.coli infection, lipoprotein and LPS could additively induce Fas L expression on NK1.1^+ T cells, leading to liver injury in vivo in normal mice but not in gld/gld mice. In conclusion, it is suggested that induction of Fas L on NK T cells in response to bacterial components such as lipoproteins plays an important role in pathogenesis of E.coli-induced liver injury in mice. Less
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