| Budget Amount *help |
¥15,600,000 (Direct Cost: ¥15,600,000)
Fiscal Year 2004: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2003: ¥12,300,000 (Direct Cost: ¥12,300,000)
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| Research Abstract |
In this study, we have investigated the mechanisms for the immunological abnormalities that had been observed in mice lacking the transcription factor interferon regulatory factor-2 (IRF-2). First, we found that the subset of dendritic cells (DC) bearing CD4 were greatly reduced compared with those in control mice in the spleen and epidermis in these mice. Such a reduction appeared to be due to cell intrinsic defect of IRF-2 in bone marrow cells as indicated in radiation bone marrow (BM) chimeras. Notably, type I interferon signaling were indispensable for the DC phenotype as double mutant mice lacking both IRF-2 and the type I interferon receptor did not show such a phenotype, suggesting that IRF-2 is important for repressing interferon signals, thereby allowing CD4+ DC subset to develop. In these double mutant mice, the skin inflammation developing spontaneously in IRF-2-deficient mice was no longer observed. These observations pointed to an interesting possibility that the abnormali
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ty in CD4+ DC subset might contribute to the skin pathogenesis. Furthermore, with respect to another immunological abnormality in IRF-2-deficient mice, NK cell deficiency, we showed that IRF-2 functioned at a late step during NK cell development, and only immature NK cells were remaining in the BM in IRF-2-deficient mice. Curiously, residual NK cells in the spleen were even less mature than those in the bone marrow in these mice as judged from the expression patterns of Ly49 and other cell surface markers. This differential NK cell maturation arrest was due to accelerated apoptosis of NK cells in the BM, which prevented relatively mature BM NK cells to exit to the periphery. Finally, we identified abnormal basophil expansion as a mechanism for the Th2-biased immune responses observed in IRF-2-deficient mice. NK cell deficiency and basophil expansion was also observed in the double mutant mice mentioned above, indicating that NK cell development and basophil homeostasis were regulated in a different way than CD4+ DC development. Less
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