Reiter Z
Division of Morphological Sciences, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa.
J Interferon Res. 1993 Aug;13(4):247-57. doi: 10.1089/jir.1993.13.247.
Natural killer (NK) cells probably function as an early defense line against viruses because of their ability to kill virus-infected cells as well as a variety of tumor cells. In both cases, the killing is major histocompatibility complex (MHC)-unrestricted. NK cells exhibit spontaneous activity but they are positively regulated by interferons (IFNs) or indirectly by such IFN inducers as viruses, bacterial products, poly(rI):(rC), and mitogens. In addition to their "positive" regulation on NK activity, IFNs often act as "negative signals" for NK and lymphokine-activated killer (LAK) cell-mediated cytotoxicity. If NK susceptible target cells are exposed to IFN prior to NK cells, their sensitivity to NK activity is often markedly diminished. The mechanism by which IFNs (IFN-alpha, -beta, and -gamma) affect the sensitivity of target cells to NK activity remains unknown, but it is clear that this function is not shared by other cell-mediated killing processes. The protective effect induced by IFN against NK activity is dependent on new mRNA and protein synthesis and can be abolished when target cells are incubated with a combination of IFN and metabolic inhibitors or by chemotherapeutic purine or pyrimidine analogs. IFN treatment neither affects the conjugate formation between NK cell and target cell nor the susceptibility of target cells to NK cytotoxic factor (NKCF), released by effector cells. However, IFN reduces the capacity of target cells to induce activation of conjugated NK cells. Because IFN has the ability to induce or increase class I MHC antigen expression (on NK target cells), it has been suggested that class I MHC antigens act as "negative signals" or NK-mediated cytotoxicity. Although many studies support this hypothesis, others present evidence for a lack of involvement of class I MHC antigens in mediating sensitivity to NK activity. This review summarizes and discusses the dual effect of IFNs in the regulation of NK activity, the relationship between the expression of class I MHC antigens on target cell surface and sensitivity to NK activity following treatment with IFNs, and the possible clinical relevance of the dual effect of IFN.
自然杀伤（NK）细胞可能作为抵御病毒的早期防线，因为它们能够杀死病毒感染细胞以及多种肿瘤细胞。在这两种情况下，杀伤作用都是主要组织相容性复合体（MHC）非限制性的。NK细胞表现出自发活性，但它们受到干扰素（IFN）的正向调节，或受到病毒、细菌产物、聚肌苷酸：聚胞苷酸（poly(rI):(rC)）和丝裂原等IFN诱导剂的间接调节。除了对NK活性的“正向”调节外，IFN通常还作为NK和淋巴因子激活的杀伤细胞（LAK）介导的细胞毒性的“负信号”。如果NK敏感靶细胞在NK细胞之前暴露于IFN，它们对NK活性的敏感性通常会显著降低。IFN（IFN-α、-β和-γ）影响靶细胞对NK活性敏感性的机制尚不清楚，但很明显，这种功能并非其他细胞介导的杀伤过程所共有。IFN诱导的对NK活性的保护作用依赖于新的mRNA和蛋白质合成，当靶细胞与IFN和代谢抑制剂的组合孵育时，或用化疗嘌呤或嘧啶类似物处理时，这种保护作用可以被消除。IFN处理既不影响NK细胞与靶细胞之间的共轭形成，也不影响靶细胞对效应细胞释放的NK细胞毒性因子（NKCF）的敏感性。然而，IFN降低了靶细胞诱导共轭NK细胞激活的能力。由于IFN能够诱导或增加I类MHC抗原的表达（在NK靶细胞上），有人提出I类MHC抗原作为“负信号”或NK介导的细胞毒性。尽管许多研究支持这一假设，但也有其他研究表明I类MHC抗原与介导对NK活性的敏感性无关。这篇综述总结并讨论了IFN在调节NK活性中的双重作用、靶细胞表面I类MHC抗原表达与IFN处理后对NK活性敏感性之间的关系，以及IFN双重作用的可能临床相关性。
