Molecular mechanism of measles virus-induced immunosuppression

小鼠成纤维细胞系（L, NIH3T3）支持低水平的麻疹病毒（MV）复制。这些成纤维细胞从未形成多核巨细胞，这是MV感染的典型细胞病变效应。我们获得了稳定表达人类CD46基因的L细胞转染物，CD46是最近发现的MV受体。感染MV后，这些转染物产生的MV是亲本L细胞的20倍，对MV的敏感性是亲本L细胞的100倍，并形成合胞体。为了确定CD46中受体功能所必需的结构域，产生了几个缺失突变体，这些突变体缺乏细胞质区域或CD46的四个短一致重复（SCR）中的每一个。缺乏sc1或SCR2的突变体不作为受体，这表明sc1或SCR2对于MV受体的功能是必不可少的。在这些结果的基础上，我们制作了表达人CD46的转基因小鼠作为动物模型来研究MV感染期间观察到的免疫抑制。我们目前正在测试这些小鼠是否对MV易感，并出现任何临床症状。我们还研究了MV抑制T细胞体外增殖的机制。与表达MV糖蛋白但不产生感染性MV的细胞共培养，没有导致丝裂原诱导的T细胞增殖受到抑制，这表明通过MV感染细胞上表达的MV糖蛋白和未感染细胞上表面分子的细胞间相互作用不足以引起T细胞增殖的抑制。

Mouse fibroblast cell lines (L, NIH3T3) supported a low level of measles virus (MV) replication. These fibroblasts never formed multinucleated giant cells, a characteristic cytopathic effect of MV infection. We derived L cell transfectants stably expressing the gene encoding the human CD46, the recently identified MV receptor. Upon infection with MV, these transfectants produced 20 fold more MV, became 100 time more sensitive to MV than the parental L cells, and developed syncytia. To determine the domain (s) in CD46 essential for the receptor function, several deletion mutants were generated that lacked the cytoplasmic region or each one of the four short consensus repeat (SCR) of CD46. Mutants lacking SCR1 or SCR2 were found not to act as the receptor, indicating that SCR1 or SCR2 are indispensable for the function as the MV receptor. On the basis of these results, we produced transgenic mice expressing the human CD46 as an animal model to study immunosuppression observed during MV infection. We are currently testing whether these mice are susceptible to MV, and develop any clinical signs.We also examined the mechanism by which MV inhibitits thein vitro proliferation of T cells. Coculture with cells expressing MV glycoproteins without producing infectious MV did not lead to the inhibition of the mitogen-induced T cell proliferation, indicating that the cell-cell interaction through MV glycoproteins expressed on MV-infected cells and surface molecules on uninfected cells is not sufficient to cause the inhibition of T cell proliferation.