Section of Immunobiology, Division of Immunology and Inflammation, Department of Medicine, Faculty of Medicine, Imperial College London, London, UK.
Immunol Lett. 2013 Apr;152(1):65-76. doi: 10.1016/j.imlet.2013.04.004. Epub 2013 Apr 25.
Serine proteases control a wide variety of physiological and pathological processes in multi-cellular organisms, including blood clotting, cancer, cell death, osmo-regulation, tissue re-modeling and immunity to infection. T lymphocytes are required for adaptive cell mediated immunity and serine proteases are not only important for effector function but also homeostatic regulation of cell numbers. Serine Protease Inhibitors (Serpins) are the physiological regulators of serine proteases activity. In this review, I will discuss the role of serpins in controlling the recognition of antigen, effector function and homeostatic control of T lymphocytes through the inhibition of physiological serine protease targets. An emerging view of serpins is that they are important promoters of cellular viability through their inhibition of executioner proteases. This will be discussed in the context of the T lymphocyte survival during effector responses and the development and persistence of long-lived memory T cells. The potent anti-apoptotic properties of serpins can also work against adaptive cell immunity by protecting viruses and tumors from eradication by cytotoxic T cells (CTL). Recent insights from knock-out mouse models demonstrate that these serpins also are required for hematological progenitor cells and so are critical for the development of lineages other than T lymphocytes. Given the emerging role of serpins in multiple aspects of lymphocyte immunity and blood development I will review the progress to date in developing new immunotherapeutic approaches based directly on serpins or knowledge gained from identifying their physiologically relevant protease targets.
丝氨酸蛋白酶在多细胞生物中控制着广泛的生理和病理过程，包括血液凝固、癌症、细胞死亡、渗透调节、组织重塑和抗感染免疫。T 淋巴细胞是适应性细胞介导免疫所必需的，丝氨酸蛋白酶不仅对效应功能很重要，而且对细胞数量的体内平衡调节也很重要。丝氨酸蛋白酶抑制剂（Serpins）是丝氨酸蛋白酶活性的生理调节剂。在这篇综述中，我将讨论 Serpins 通过抑制生理丝氨酸蛋白酶靶标，在控制抗原识别、效应功能和 T 淋巴细胞体内平衡控制中的作用。Serpins 的一个新观点是，它们通过抑制执行蛋白酶而成为细胞活力的重要促进剂。这将在效应反应过程中 T 淋巴细胞存活以及长寿命记忆 T 细胞的发展和持续存在的背景下进行讨论。Serpins 的强大抗凋亡特性也可以通过保护病毒和肿瘤免受细胞毒性 T 细胞（CTL）的清除来对抗适应性细胞免疫。来自敲除小鼠模型的最新见解表明，这些 Serpins 对于造血祖细胞也是必需的，因此对于除 T 淋巴细胞以外的谱系的发育至关重要。鉴于 Serpins 在淋巴细胞免疫和血液发育的多个方面的新兴作用，我将回顾迄今为止在基于 Serpins 或从鉴定其生理相关蛋白酶靶标中获得的知识直接开发新免疫治疗方法方面的进展。
