Liu C C, Persechini P M, Young J D
Laboratory of Molecular Immunology and Cell Biology, Rockefeller University, New York 10021, USA.
Immunol Rev. 1995 Aug;146:145-75. doi: 10.1111/j.1600-065x.1995.tb00688.x.
We have discussed in the previous sections the recent progress made toward elucidating the regulatory mechanism of perforin gene transcription and the domain structure of the perforin molecule. It appears that the expression of perforin is, at least partially, controlled at the transcription level through the interaction between killer cell-specific cis- and trans- acting factors. One of such cognate pairs, NF-P motif (an EBS-homologous motif) and NF-P2 (a killer cell-specific DNA-binding protein), has been described. The regulatory mechanism of gene transcription, however, is likely to involve multiple factors which act in a coordinated fashion to bring about the most efficient expression of perforin limited strictly to activated killer lymphocytes. Through studies using synthetic peptides and recombinant perforins, it has been suggested that the N-terminal region of the perforin molecule is an important, though not the only, domain responsible for the lytic activity. Further studies are warranted to elucidate the role(s) of other potential amphiphilic structures located in the central portion of the perforin molecule in the overall pore-forming activity. The molecular basis underlying the resistance of killer lymphocytes to perforin-mediated lysis still remains an open question. Preliminary results, however, suggest that the surface protein(s) restricted to killer cells may account for their self-protection against perforin. Based on recent studies using perforin-deficient mice, the involvement of perforin in lymphocyte-mediated cytolysis both in vivo and in vitro has been confirmed. Two functional roles, a direct (lytic) and an indirect (endocytosis enhancer; conduit), both of which may contribute critically to the cell-killing event can be attributed to perforin. The fact that lymphocytes may also employ perforin-independent killing mechanism(s), e.g. Fas-dependent pathway, is beyond the scope of this review. There is, nevertheless, no doubt that these alternative cytolytic mechanisms may also play important roles in immune effector and/or regulatory responses associated with killer lymphocytes. Obviously, we are still a long way from concluding on the functional relevance of each individual cytolytic mechanism seen in different physiopathological situations. Suffice it to say, however, that a wealth of information on lymphocyte-mediated killing has already emerged through the multidisciplinary efforts conducted in our and other laboratories that promise to further dissect this complicated event in the years to come.
我们已在前面的章节中讨论了在阐明穿孔素基因转录调控机制和穿孔素分子结构域方面取得的最新进展。穿孔素的表达似乎至少部分地在转录水平上通过杀伤细胞特异性顺式和反式作用因子之间的相互作用受到控制。已描述了这样一对同源物，即NF-P基序（一种EBS同源基序）和NF-P2（一种杀伤细胞特异性DNA结合蛋白）。然而，基因转录的调控机制可能涉及多种因子，它们以协调的方式发挥作用，以实现穿孔素在活化的杀伤淋巴细胞中严格受限的最有效表达。通过使用合成肽和重组穿孔素的研究表明，穿孔素分子的N端区域是负责裂解活性的一个重要结构域，尽管不是唯一的结构域。有必要进一步研究以阐明位于穿孔素分子中部的其他潜在两亲性结构在整体成孔活性中的作用。杀伤淋巴细胞对穿孔素介导的裂解具有抗性的分子基础仍然是一个悬而未决的问题。然而，初步结果表明，仅限于杀伤细胞的表面蛋白可能解释了它们对穿孔素的自我保护。基于最近对穿孔素缺陷小鼠的研究，已证实穿孔素在体内和体外淋巴细胞介导的细胞溶解中均有参与。穿孔素可发挥两种功能作用，一种是直接（裂解）作用，另一种是间接（内吞增强剂；通道）作用，这两种作用都可能对细胞杀伤事件起关键作用。淋巴细胞也可能采用不依赖穿孔素的杀伤机制，例如Fas依赖性途径，这一事实超出了本综述的范围。然而，毫无疑问，这些替代的细胞溶解机制在与杀伤淋巴细胞相关的免疫效应和/或调节反应中也可能发挥重要作用。显然，我们距离确定在不同生理病理情况下看到的每种细胞溶解机制的功能相关性还有很长的路要走。然而，仅需指出的是，通过我们实验室和其他实验室的多学科努力，已经出现了大量关于淋巴细胞介导杀伤的信息，有望在未来几年进一步剖析这一复杂事件。
