Gene Expression in Immunological Tolerance and Immune Dysfunctions Caused by Its Disturbance

在这项研究中，我们已经调查了机制的免疫异常，已观察到在小鼠缺乏转录因子干扰素调节因子-2（IRF-2）。首先，我们发现这些小鼠的脾脏和表皮中携带CD 4的树突状细胞（DC）的亚群与对照小鼠相比大大减少。这种减少似乎是由于骨髓细胞中IRF-2的细胞内在缺陷，如辐射骨髓（BM）嵌合体中所示。值得注意的是，I型干扰素信号传导对于DC表型是必不可少的，因为缺乏IRF-2和I型干扰素受体的双突变小鼠没有显示出这样的表型，这表明IRF-2对于抑制干扰素信号是重要的，从而允许CD 4 + DC亚群发育。在这些双突变小鼠中，不再观察到IRF-2缺陷小鼠中自发发生的皮肤炎症。这些观察结果指出了一种有趣的可能性， ...更多信息 CD 4 + DC亚群的异常可能参与了皮肤的发病机制。此外，关于IRF-2缺陷小鼠的另一种免疫异常，NK细胞缺陷，我们发现IRF-2在NK细胞发育的后期发挥作用，并且在IRF-2缺陷小鼠的BM中仅残留未成熟的NK细胞。奇怪的是，从Ly 49和其他细胞表面标志物的表达模式判断，这些小鼠脾脏中残留的NK细胞甚至比骨髓中的NK细胞更不成熟。这种差异性NK细胞成熟停滞是由于BM中NK细胞的加速凋亡，这阻止了相对成熟的BM NK细胞离开到外周。最后，我们确定异常嗜碱性粒细胞扩增作为IRF-2缺陷小鼠中观察到的Th 2偏向性免疫应答的机制。在上述双突变小鼠中也观察到NK细胞缺陷和嗜碱性粒细胞扩增，表明NK细胞发育和嗜碱性粒细胞稳态的调节方式与CD 4 + DC发育不同。少

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 … More 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