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 Aug 1;189(3):1133-43. doi: 10.4049/jimmunol.1003406. Epub 2012 Jun 27.
The persistence of memory T lymphocytes confers lifelong protection from pathogens. Memory T cells survive and undergo homeostatic proliferation (HSP) in the absence of Ag, although the cell-intrinsic mechanisms by which cytokines drive the HSP of memory T cells are not well understood. In this study we report that lysosome stability limits the long-term maintenance of memory CD8(+) T cell populations. Serine protease inhibitor (Spi) 2A, an anti-apoptotic cytosolic cathepsin inhibitor, is induced by both IL-15 and IL-7. Mice deficient in Spi2A developed fewer memory phenotype CD44(hi)CD8(+) T cells with age, which underwent reduced HSP in the bone marrow. Spi2A was also required for the maintenance of central memory CD8(+) T cell populations after acute infection with lymphocytic choriomeningitis virus. Spi2A-deficient Ag-specific CD8(+) T cell populations declined more than wild-type competitors after viral infection, and they were eroded further after successive infections. Spi2A protected memory cells from lysosomal breakdown by inhibiting cathepsin B. The impaired maintenance of Spi2A-deficient memory CD8(+) T cells was rescued by concomitant cathepsin B deficiency, demonstrating that cathepsin B was a physiological target of Spi2A in memory CD8(+) T cell survival. Our findings support a model in which protection from lysosomal rupture through cytokine-induced expression of Spi2A determines the long-term persistence of memory CD8(+) T cells.
记忆 T 淋巴细胞的持久性赋予了它们免受病原体侵害的终身保护。记忆 T 细胞在没有抗原的情况下存活并进行同源性增殖（HSP），尽管细胞内因子驱动记忆 T 细胞 HSP 的细胞内机制尚未得到很好的理解。在这项研究中，我们报告溶酶体稳定性限制了记忆 CD8(+) T 细胞群体的长期维持。丝氨酸蛋白酶抑制剂（Spi）2A 是一种抗凋亡的细胞质组织蛋白酶抑制剂，可被 IL-15 和 IL-7 诱导。缺乏 Spi2A 的小鼠随着年龄的增长会产生较少的记忆表型 CD44(hi)CD8(+)T 细胞，这些细胞在骨髓中的 HSP 减少。Spi2A 对于淋巴细胞性脉络丛脑膜炎病毒急性感染后中央记忆 CD8(+)T 细胞群体的维持也是必需的。Spi2A 缺陷的 Ag 特异性 CD8(+)T 细胞群体在病毒感染后比野生型竞争者下降得更多，并且在连续感染后进一步被侵蚀。Spi2A 通过抑制组织蛋白酶 B 来保护记忆细胞免受溶酶体破裂的影响。同时缺乏组织蛋白酶 B 可挽救 Spi2A 缺陷的记忆 CD8(+)T 细胞的维持缺陷，表明组织蛋白酶 B 是 Spi2A 在记忆 CD8(+)T 细胞存活中的生理靶点。我们的研究结果支持这样一种模型，即通过细胞因子诱导的 Spi2A 表达来防止溶酶体破裂，从而决定了记忆 CD8(+)T 细胞的长期持久性。
