Immunoproteasomes largely replace constitutive proteasomes during an antiviral and antibacterial immune response in the liver
Immunoproteasomes largely replace constitutive proteasomes during an antiviral and antibacterial immune response in the liver
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DOI：
10.4049/jimmunol.167.12.6859
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发表时间：
2001-12-15
影响因子：
4.4
通讯作者：
Groettrup, M
中科院分区：
文献类型：
--
作者：
Khan, S;van den Broek, M;Groettrup, M
蛋白酶体在MHC I类限制性T细胞表位的产生中起关键作用。蛋白酶体活性和表位产生通过IFN-γ处理而改变，这导致体外免疫蛋白酶体逐渐取代组成型蛋白酶体。然而，在体内针对病毒或细菌的免疫应答期间蛋白酶体的稳态亚基组成的变化的定量分析尚未报道。在这里，我们表明，小鼠感染淋巴细胞性脉络丛脑膜炎病毒或单核细胞增生李斯特菌导致组成型蛋白酶体在肝脏中的免疫蛋白酶体在7天内几乎完全取代。蛋白酶体替代在IFN-γ（-/-）小鼠中显著减少，但在IFN-α R（-/-）和perform（-/-）小鼠中仅受到轻微影响。在淋巴细胞性脉络丛脑膜炎病毒感染小鼠的肝脏中，蛋白酶体调节剂PA 28 α/β上调，而PA 28 γ降低。肝脏中的蛋白酶体替代强烈改变了蛋白酶体活性，并且在这种程度上是出乎意料的，因为先前已将12天的体内半衰期指定给肝脏中的组成性蛋白酶体。我们的研究结果表明，在病毒和细菌清除的高峰期，抗病毒细胞毒性T淋巴细胞反应主要是针对免疫蛋白酶体依赖性T细胞表位，这将是一个新的参数的疫苗设计。
The proteasome is critically involved in the production of MHC class I-restricted T cell epitopes. Proteasome activity and epitope production are altered by IFN-gamma treatment, which leads to a gradual replacement of constitutive proteasomes by immunoproteasomes in vitro. However, a quantitative analysis of changes in the steady state subunit composition of proteasomes during an immune response against viruses or bacteria in vivo has not been reported. Here we show that the infection of mice with lymphocytic choriomeningitis virus or Listeria monocytogenes leads to an almost complete replacement of constitutive proteasomes by immunoproteasomes in the liver within 7 days. Proteasome replacements were markedly reduced in IFN-gamma (-/-) mice, but were only slightly affected in IFN-alphaR(-/-) and perform(-/-) mice. The proteasome regulator PA28 alpha/beta was up-regulated, whereas PA28 gamma was reduced in the liver of lymphocytic choriomeningitis virus-infected mice. Proteasome replacements in the liver strongly altered proteasome activity and were unexpected to this extent, since an in vivo half-life of 12 days had been previously assigned to constitutive proteasomes in the liver. Our results suggest that during the peak phase of viral and bacterial elimination the antiviral cytotoxic T lymphocyte response is directed mainly to immunoproteasome-dependent T cell epitopes, which would be a novel parameter for the design of vaccines.