Murphy S P, Tomasi T B
Department of Immunology, Laboratory of Molecular Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Mol Reprod Dev. 1998 Sep;51(1):1-12. doi: 10.1002/(SICI)1098-2795(199809)51:1<1::AID-MRD1>3.0.CO;2-L.
Although the mechanism(s) underlying the failure of the maternal immune system to reject the semiallogeneic fetus have not been clearly defined, the absence of MHC class II antigen expression by fetal trophoblast cells very likely plays a critical role in the maintenance of normal pregnancy. However, the regulation of class II antigen expression in trophoblast cells is poorly understood. Class II transactivator (CIITA) is a transacting factor that is required for both constitutive and IFN-gamma-inducible class II gene transcription. In this report we demonstrate that the inability of trophoblast cells to express class II antigens is due to a lack of CIITA gene expression. Trophoblast cell lines derived from human, mouse, and rat do not express CIITA, and expression is not inducible by IFN-gamma. The absence of CIITA gene expression in trophoblasts treated with IFN-gamma does not result from a defect in the IFN-gamma receptor or the JAK/STAT pathway, because the classical IFN-gamma inducible gene encoding the guanylate-binding protein is expressed. Transfection of CIITA expression vectors into trophoblast cells results in activation of class II promoters, endogenous class II mRNA expression, and subsequent expression of class II antigens on the cell surface. In contrast, class I mRNA is not expressed in human trophoblast cells transfected with CIITA expression vectors. Thus, trophoblast cells contain all of the DNA binding factors necessary for class II transcription, and ectopic expression of CIITA is sufficient to activate class II, but not class I expression. The failure of trophoblast cells to express CIITA, and therefore class II antigens, provides a potential mechanism by which the fetus is protected from the maternal immune system during pregnancy.
尽管母体免疫系统未能排斥半同种异体胎儿的潜在机制尚未明确，但胎儿滋养层细胞缺乏MHC II类抗原表达很可能在维持正常妊娠中起关键作用。然而，滋养层细胞中II类抗原表达的调控却知之甚少。II类反式激活因子（CIITA）是一种反式作用因子，对于组成型和IFN-γ诱导型II类基因转录都是必需的。在本报告中，我们证明滋养层细胞无法表达II类抗原是由于缺乏CIITA基因表达。源自人、小鼠和大鼠的滋养层细胞系不表达CIITA，且其表达不能被IFN-γ诱导。用IFN-γ处理的滋养层细胞中CIITA基因表达的缺失并非源于IFN-γ受体或JAK/STAT途径的缺陷，因为编码鸟苷酸结合蛋白的经典IFN-γ诱导基因是表达的。将CIITA表达载体转染到滋养层细胞中会导致II类启动子激活、内源性II类mRNA表达以及随后细胞表面II类抗原的表达。相反，在转染了CIITA表达载体的人滋养层细胞中不表达I类mRNA。因此，滋养层细胞含有II类转录所需的所有DNA结合因子，CIITA的异位表达足以激活II类而非I类表达。滋养层细胞无法表达CIITA，进而无法表达II类抗原，这为胎儿在妊娠期间免受母体免疫系统攻击提供了一种潜在机制。
