Serglycin-deficient cytotoxic T lymphocytes display defective secretory granule maturation and granzyme B storage
Serglycin-deficient cytotoxic T lymphocytes display defective secretory granule maturation and granzyme B storage
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DOI：
10.1074/jbc.m501708200
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发表时间：
2005-09-30
影响因子：
4.8
通讯作者：
Åbrink, M
中科院分区：
文献类型：
--
作者：
Grujic, M;Braga, T;Åbrink, M
细胞毒性T淋巴细胞主要通过穿孔素/颗粒酶诱导的细胞凋亡来清除感染细胞和肿瘤细胞。早期的研究表明，serglycine - proteglycans与颗粒酶和穿孔素在细胞毒性颗粒中形成大分子复合物。甘油蛋白聚糖也可能参与细胞溶解机制进入靶细胞的传递。我们开发了一种serglycine -deficient小鼠品系，在这里我们研究了serglycine - proteglycans在细胞毒性T淋巴细胞功能的各个方面的重要性。（SO42-）- s -35放射性标记显示，与野生型细胞相比，serglycin缺陷细胞的合并标记显著减少，这表明serglycin是迄今为止细胞毒性T淋巴细胞产生的主要蛋白聚糖种类。此外，缺乏serglycin导致细胞毒性T淋巴细胞产生高电子密度分泌颗粒的能力受损，尽管野生型和serglycin缺乏的细胞都能产生低电子密度的颗粒。谢尔甘霉素缺乏不影响颗粒酶A、颗粒酶B或穿孔素的mRNA表达。然而，在serglycin缺乏的细胞中，颗粒酶B的储存存在严重缺陷，而颗粒酶A、Fas配体或穿孔素的储存则没有。serglycin缺陷细胞对靶细胞系的晚期细胞毒性没有表现出缺陷。综上所述，这些结果表明serglycin在颗粒酶B的储存和分泌颗粒成熟中起关键作用，但反对serglycin在细胞毒性T淋巴细胞介导的细胞凋亡中起主要作用。
Cytotoxic T lymphocytes eliminate infected and tumor cells mainly by perforin/granzyme-induced apoptosis. Earlier studies suggested that serglycin-proteoglycans form macromolecular complexes with granzymes and perforin in the cytotoxic granule. Serglycin-proteoglycans may also be involved in the delivery of the cytolytic machinery into target cells. We have developed a serglycin-deficient mouse strain, and here we studied the importance of serglycin-proteoglycans for various aspects of cytotoxic T lymphocyte function. (SO42-)-S-35 radiolabeling of serglycin-deficient cells demonstrated a dramatic reduction of incorporated label as compared with wild type cells, indicating that serglycin is by far the dominating proteoglycan species produced by the cytotoxic T lymphocyte. Moreover, lack of serglycin resulted in impaired ability of cytotoxic T lymphocytes to produce secretory granule of high electron density, although granule of lower electron density were produced both in wild type and serglycin-deficient cells. The serglycin deficiency did not affect the mRNA expression for granzyme A, granzyme B, or perforin. However, the storage of granzyme B, but not granzyme A, Fas ligand, or perforin, was severely defective in serglycin-deficient cells. Serglycin-deficient cells did not display defects in late cytotoxicity toward target cell lines. Taken together, these results point to a key role for serglycin in the storage of granzyme B and for secretory granule maturation but argue against a major role for serglycin in the apoptosis mediated by cytotoxic T lymphocytes.