Department of Signaling and Gene Expression, The La Jolla Institute of Allergy and Immunology, La Jolla, CA 92037, USA.
Immunol Rev. 2010 May;235(1):55-72. doi: 10.1111/j.0105-2896.2010.00905.x.
Natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) use cytotoxic granules containing perforin and granzymes to lyse infected or malignant host cells, thereby providing immunity to intracellular microbes and tumors. Perforin is essential for cytotoxic granule-mediated killing. Perforin expression is regulated transcriptionally and correlates tightly with the development of cells that can exhibit cytotoxic activity. Although a number of genes transcribed by T cells and NK cells have been studied, the cell-specificity of perforin gene expression makes it an ideal model system in which to clarify the transcriptional mechanisms that guide the development and activation of cytotoxic lymphocytes. In this review, we discuss what is known about perforin expression and its regulation, then elaborate on recent studies that utilized chromosome transfer and bacterial artificial chromosome transgenics to define a comprehensive set of cis-regulatory regions that control transcription of the human PRF1 gene in a near-physiologic context. In addition, we compare the human and murine Prf1 loci and discuss how transcription factors known to be important for driving CTL differentiation might also directly regulate the cis-acting domains that control Prf1. Our review emphasizes how studies of PRF1/Prf1 gene transcription can illuminate not only the mechanisms of cytotoxic lymphocyte differentiation but also some basic principles of transcriptional regulation.
自然杀伤 (NK) 细胞和细胞毒性 T 淋巴细胞 (CTL) 使用含有穿孔素和颗粒酶的细胞毒性颗粒裂解受感染或恶性宿主细胞，从而提供对细胞内微生物和肿瘤的免疫力。穿孔素对于细胞毒性颗粒介导的杀伤是必不可少的。穿孔素的表达受转录调控，并与能够表现出细胞毒性活性的细胞的发育密切相关。尽管已经研究了许多由 T 细胞和 NK 细胞转录的基因，但穿孔素基因表达的细胞特异性使其成为阐明指导细胞毒性淋巴细胞发育和激活的转录机制的理想模型系统。在这篇综述中，我们讨论了已知的穿孔素表达及其调控，然后详细介绍了最近的研究，这些研究利用染色体转移和细菌人工染色体转基因来定义一套全面的顺式调控区，以在近生理条件下控制人类 PRF1 基因的转录。此外，我们比较了人和鼠的 Prf1 基因座，并讨论了已知对驱动 CTL 分化很重要的转录因子如何也直接调节控制 Prf1 的顺式作用域。我们的综述强调了 PRF1/Prf1 基因转录的研究不仅可以阐明细胞毒性淋巴细胞分化的机制，还可以阐明转录调控的一些基本原则。
