| Budget Amount *help |
¥14,000,000 (Direct Cost: ¥14,000,000)
Fiscal Year 2003: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 2002: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Research Abstract |
Dendritic cells (DC) are divided into several subsets by their phenotype and developmental lineage and their functions are controlled under physiological milieu. In this study, we conducted experiments to elucidate role of DC in the control of immune responses in vivo and obtained the following results.
1) Significant deviation toward Th2 was observed in Id2^<-/->. We found that a selective and remarkable reduction of the CD8α^+ DC subset, which has higher potential to produce IL-12 than the CD8α^-DC subset. These results demonstrate that Id2 is indispensable for the proper development of CD8α^+ DCs, which play a critical role in the regulation of the Th1/Th2 balance.
2) Mice lacking IRF-2 (IRF-2-/-mice) exhibited a marked and selective defect in the development of splenic CD4^+ CD11b^+ DC. Furthermore, the numbers of epidermal Langerhans cells in IRF-2^<-/-> mice were reduced. Studies with in vitro retrovirus-mediated gene transduction showed that IRF-2 was required cell-autonomously fo
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r the development of CD4^+ CD11b^+ DC. Notably, these abnormalities in DC subpopulations diminished in mice lacking both IRF-2 and the IFN-α/β receptor, indicating that IRF-2 acted through negatively IFN-α/β signals.
3) The CFSE-labeled apoptotic cells were actively endocytosed by DCs in vivo, but only the CD8α^+ subset. Following uptake, CD8α^+ DCs also selectively present cell-associated antigens to both CD4^+ and CD8^+ T cells. Similar events take place with cultured. DCs ; CD8α+ DCs again selectively take up and present dying cells. In contrast, both CD8α^+ and CD8α^-DCs phagocytose latex particles in culture, and both DC subsets present soluble ovalbumin captured in vivo.
4) Following ingestion of the dead cells by DC in situ, large numbers of antigen-reactive T lymphocytes were driven into cell cycle, but then the T cells were deleted and the animals become tolerant. This, pathway to unresponsiveness should prevent or reduce the development of autoimmunity when dying cells are subsequently processed during infection.
5) We investigated the Th-polarizing capacity of P-preDC after culture with stimuli. IL-3-treated DC expressed OX40L but produced almost no IFN-α, resulting in the preferential priming of IL-4-producing Th2 cells through OX40L-dependent mechanisms. In contrast, DC by viral infection promoted IFN-γ-producing Th1 cells, depending on their capacity to produce IFN-α, although they simultaneously expressed OX40L. However, the expression level of OX40L was upregulated whereas the, residual IFN-α producing ability was downregulated during activation and, consequently, the DC with prolonged SV stimulation induced Th2 responses to some extent. Less
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