Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
Department of Emerging Pathogens and Immunity, John Curtin School for Medical Research, Australian National University, Canberra, ACT, Australia.
Immunol Cell Biol. 2017 Nov;95(10):884-894. doi: 10.1038/icb.2017.59. Epub 2017 Aug 15.
Intracellular serpins are proposed to inactivate proteases released from lysosome-related organelles into the host cell interior, preventing cell death. Serpinb9 opposes the immune cytotoxic protease, granzyme B, and in a number of settings protects cells against granzyme B-mediated cell death. Using a knockout mouse line engineered to express green fluorescent protein under the serpbinb9 promoter, we demonstrate that serpinb9 is vital for host survival during Ectromelia virus infection by maintaining both mature natural killer NK) cells, and activated CD8 T cells. Serpinb9 expression parallels granzyme B expression within both populations during infection. Maturing serpinb9-null NK cells exhibit higher levels of granzyme B-mediated apoptosis during infection; hence there are fewer mature NK cells, and these cells also have lower cytotoxic potential. Thus the serpinb9-granzyme B axis is important for homeostasis of both major cytotoxic effector cell populations.
细胞内丝氨酸蛋白酶抑制剂被认为可以使从溶酶体相关细胞器释放到宿主细胞内部的蛋白酶失活，从而防止细胞死亡。Serpinb9 可以对抗免疫细胞毒性蛋白酶 granzyme B，并在许多情况下保护细胞免受 granzyme B 介导的细胞死亡。我们使用一种经过基因工程改造的敲除小鼠系，使其在 serpbinb9 启动子的控制下表达绿色荧光蛋白，证明在 Ectromelia 病毒感染期间，serpinb9 通过维持成熟自然杀伤 (NK) 细胞和激活的 CD8 T 细胞对宿主的存活至关重要。在感染过程中，Serpinb9 的表达与这两种细胞群中的 granzyme B 表达平行。成熟的 serpinb9 缺陷型 NK 细胞在感染期间表现出更高水平的 granzyme B 介导的细胞凋亡；因此，成熟的 NK 细胞数量减少，这些细胞的细胞毒性潜力也较低。因此，serpinb9-granzyme B 轴对于两种主要细胞毒性效应细胞群的稳态都很重要。
