NK Cell Maturation and Cytotoxicity Are Controlled by the Intramembrane Aspartyl Protease SPPL3.
NK Cell Maturation and Cytotoxicity Are Controlled by the Intramembrane Aspartyl Protease SPPL3.
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DOI：
10.4049/jimmunol.1501970
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发表时间：
2016-03-15
期刊：
影响因子：
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通讯作者：
Pomerantz JL
中科院分区：
文献类型：
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作者：
Hamblet CE;Makowski SL;Tritapoe JM;Pomerantz JL
NK细胞成熟对于正常的效应功能和对肿瘤和病原体的先天免疫反应至关重要。然而，控制NK细胞成熟的分子途径在很大程度上仍然不明确。在这里，我们研究了SPPL3（一种膜内天冬氨酸蛋白酶）在小鼠NK细胞生物学中的作用。我们发现造血系统中SPPL3的缺失减少了外周NK细胞的数量，体内MHC i类缺陷肿瘤的清除，以及体外对肿瘤细胞的细胞毒性。这种表型伴随着CD27+CD11b+和CD27−CD11b+ NK细胞数量的减少，表明SPPL3在NK细胞的有效成熟中是必需的。NK细胞特异性的SPPL3缺失会导致同样的缺陷，揭示了SPPL3在这些过程中的细胞自主作用。在小鼠受精卵中使用CRISPR/Cas9基因组编辑来产生具有催化受损SPPL3 D271A等位基因的敲入小鼠。在NK细胞中仅表达SPPL3 D271A的小鼠表型上缺失了SPPL3，表明NK细胞生物学中需要SPPL3蛋白酶活性。我们的研究结果确定SPPL3是NK细胞成熟的细胞自主分子决定因素，并扩大了膜内天冬氨酸蛋白酶在先天免疫中的作用。
NK cell maturation is critical for normal effector function and the innate immune response to tumors and pathogens. However, the molecular pathways that control NK cell maturation remain largely undefined. Here, we investigate the role of SPPL3, an intramembrane aspartyl protease, in murine NK cell biology. We find that deletion of SPPL3 in the hematopoietic system reduces numbers of peripheral NK cells, clearance of MHC Class I-deficient tumors in vivo, and cytotoxicity against tumor cells in vitro. This phenotype is concomitant with reduced numbers of CD27+CD11b+ and CD27−CD11b+ NK cells, indicating a requirement for SPPL3 in efficient NK cell maturation. NK cell-specific deletion of SPPL3 results in the same deficiencies, revealing a cell-autonomous role for SPPL3 in these processes. CRISPR/Cas9 genomic editing in murine zygotes was used to generate knock-in mice with a catalytically compromised SPPL3 D271A allele. Mice engineered to express only SPPL3 D271A in NK cells phenocopy mice deleted for SPPL3, indicating a requirement for SPPL3 protease activity in NK cell biology. Our results identify SPPL3 as a cell-autonomous molecular determinant of NK cell maturation and expand the role of intramembrane aspartyl proteases in innate immunity.