Active and zymogen forms of granzyme B are constitutively released from cytotoxic lymphocytes in the absence of target cell engagement
Active and zymogen forms of granzyme B are constitutively released from cytotoxic lymphocytes in the absence of target cell engagement
复制标题
DOI：
10.1038/icb.2008.98
复制
发表时间：
2009-03-01
影响因子：
4
通讯作者：
Bird, Phillip I.
中科院分区：
文献类型：
--
作者：
Prakash, Monica D.;Bird, Catherina H.;Bird, Phillip I.
颗粒酶B（GrB）在细胞毒性淋巴细胞（CL）介导的异常细胞杀伤中发挥着公认的细胞内作用;然而，新出现的证据表明，它通过失巢凋亡参与细胞外基质重塑和靶细胞破坏。由于这些过程需要将GrB从CL释放到细胞外环境中，因此我们检查了GrB从自然杀伤（NK）细胞和细胞毒性T淋巴细胞（CTL）的分泌。我们发现，在没有靶细胞参与的情况下，CTL和NK细胞组成性分泌一定比例的GrB。在NK细胞中，蛋白酶主要通过分泌颗粒以活性形式释放。相比之下，T淋巴细胞主要分泌无活性的GrB酶原，绕过颗粒。GrB通过两种途径从未缀合的CL释放表明，它在细胞外发挥作用，并且可能在免疫失调的情况下导致病理学改变，例如家族性噬血细胞性淋巴组织细胞增生症（FHL）。我们的研究结果还预测存在GrB的细胞外激活剂。
Granzyme B (GrB) plays a well-established intracellular role in cytotoxic lymphocyte (CL)-mediated killing of abnormal cells; however, emerging evidence suggests that it participates in extracellular matrix remodeling and target cell destruction through anoikis. As these processes require the release of GrB from the CL into the extracellular environment, we examined the secretion of GrB from natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). We found that a proportion of GrB is constitutively secreted by both CTLs and NK cells in the absence of target cell engagement. In NK cells, the protease is primarily released in an active form through secretory granules. By contrast, T lymphocytes primarily secrete inactive GrB zymogen, bypassing the granules. The release of GrB through two routes from unconjugated CLs suggests that it functions outside the cell and may contribute to pathology in cases of immune dysregulation, such as familial hemophagocytic lymphohistiocytosis (FHL). Our findings also predict the existence of an extracellular activator of GrB.