Section of Immunobiology, Division of Immunology and Inflammation, Department of Medicine, Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom.
J Immunol. 2012 Feb 1;188(3):1057-63. doi: 10.4049/jimmunol.1102667. Epub 2012 Jan 6.
How dendritic cells (DC) present Ag to cytotoxic T cells (CTL) without themselves being killed through contact-mediated cytotoxicity (so-called kiss of death) has proved to be controversial. Using mice deficient in serine protease inhibitor 6 (Spi6), we show that Spi6 protects DC from the kiss of death by inhibiting granzyme B (GrB) delivered by CTL. Infection of Spi6 knockout mice with lymphocytic choriomeningitis virus revealed impaired survival of CD8α DC. The impaired survival of Spi6 knockout CD8α DC resulted in impaired priming and expansion of both primary and memory lymphocytic choriomeningitis virus-specific CTL, which could be corrected by GrB deficiency. The rescue in the clonal burst obtained by GrB elimination demonstrated that GrB was the physiological target through which Spi6 protected DC from CTL. We conclude that the negative regulation of DC priming of CD8 T lymphocyte immunity by CTL killing is mitigated by the physiological inhibition of GrB by Spi6.
树突状细胞 (DC) 如何在不通过接触介导的细胞毒性 (所谓的死亡之吻) 自身被杀死的情况下将 Ag 呈递给细胞毒性 T 细胞 (CTL)，这一直存在争议。我们使用缺乏丝氨酸蛋白酶抑制剂 6 (Spi6) 的小鼠表明，Spi6 通过抑制 CTL 递呈的颗粒酶 B (GrB) 来保护 DC 免受死亡之吻的影响。感染淋巴细胞性脉络丛脑膜炎病毒的 Spi6 敲除小鼠显示 CD8α DC 的存活率降低。Spi6 敲除 CD8α DC 的存活率降低导致原发性和记忆性淋巴细胞性脉络丛脑膜炎病毒特异性 CTL 的启动和扩增受损，而 GrB 缺陷可纠正这种情况。GrB 消除获得的克隆爆发表明，GrB 是 Spi6 保护 DC 免受 CTL 影响的生理靶标。我们得出结论，CTL 杀伤减轻了 Spi6 对 GrB 的生理抑制，从而减轻了 DC 对 CD8 T 淋巴细胞免疫的启动负调节。
