Ca2+ signaling modulates cytolytic T lymphocyte effector functions.
Ca2+ signaling modulates cytolytic T lymphocyte effector functions.
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DOI：
10.1084/jem.187.7.1057
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发表时间：
1998-04-06
期刊：
影响因子：
--
通讯作者：
Braciale VL
中科院分区：
文献类型：
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作者：
Esser MT;Haverstick DM;Fuller CL;Gullo CA;Braciale VL
细胞溶解性T细胞使用两种机制在短期体外测定中杀死病毒感染的细胞、肿瘤细胞或其他潜在的自身反应性T细胞。穿孔素/颗粒胞吐机制使用预先形成的溶细胞颗粒，将其递送至靶细胞以诱导细胞凋亡和最终裂解。FasL/Fas（CD 95配体/CD 95）介导的细胞溶解需要CTL重新合成FasL蛋白和靶细胞上死亡受体Fas的存在以诱导凋亡。使用一个CD 8 + CTL克隆，杀死通过穿孔素/颗粒胞吐和FasL/Fas机制，和一个克隆，杀死通过FasL/Fas机制只，我们已经研究了内和细胞外Ca 2+的要求在TCR触发的细胞溶解效应功能。这两个克隆，一组的Ca 2+拮抗剂，和激动剂被用来确定，一个大的双相增加细胞内钙浓度，其特征在于释放的Ca 2+从细胞内存储，然后由持续流入的细胞外Ca 2+，是所需的穿孔素/颗粒胞吐。FasL的诱导和杀伤仅需要细胞外Ca 2+的持续流入。在低浓度下，毒胡萝卜素诱导这种小但持续的[Ca 2 +]i增加，并选择性地诱导FasL/Fas介导的细胞溶解，但不诱导颗粒胞吐。这些结果进一步确定了Ca 2+在穿孔素和FasL/Fas杀伤中的作用，并证明了差异Ca 2+信号传导可以调节T细胞效应器功能。
Cytolytic T cells use two mechanisms to kill virally infected cells, tumor cells, or other potentially autoreactive T cells in short-term in vitro assays. The perforin/granule exocytosis mechanism uses preformed cytolytic granules that are delivered to the target cell to induce apoptosis and eventual lysis. FasL/Fas (CD95 ligand/CD95)–mediated cytolysis requires de novo protein synthesis of FasL by the CTL and the presence of the death receptor Fas on the target cell to induce apoptosis. Using a CD8+ CTL clone that kills via both the perforin/granule exocytosis and FasL/Fas mechanisms, and a clone that kills via the FasL/Fas mechanism only, we have examined the requirement of intra- and extracellular Ca2+ in TCR-triggered cytolytic effector function. These two clones, a panel of Ca2+ antagonists, and agonists were used to determine that a large biphasic increase in intracellular calcium concentration, characterized by release of Ca2+ from intracellular stores followed by a sustained influx of extracellular Ca2+, is required for perforin/granule exocytosis. Only the sustained influx of extracellular Ca2+ is required for FasL induction and killing. Thapsigargin, at low concentrations, induces this small but sustained increase in [Ca2+]i and selectively induces FasL/Fas-mediated cytolysis but not granule exocytosis. These results further define the role of Ca2+ in perforin and FasL/Fas killing and demonstrate that differential Ca2+ signaling can modulate T cell effector functions.