ORAI1-mediated calcium influx is required for human cytotoxic lymphocyte degranulation and target cell lysis
ORAI1-mediated calcium influx is required for human cytotoxic lymphocyte degranulation and target cell lysis
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DOI：
10.1073/pnas.1013285108
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发表时间：
2011-02-22
影响因子：
11.1
通讯作者：
Ehl, Stephan
中科院分区：
文献类型：
--
作者：
Maul-Pavicic, Andrea;Chiang, Samuel C. C.;Ehl, Stephan
淋巴细胞通过将细胞毒性颗粒的内容物极化释放到其靶细胞来介导细胞毒性。在这里，我们研究了钙释放激活的钙通道ORAI 1在人淋巴细胞毒性中的作用。从ORAI 1缺陷患者中获得的自然杀伤（NK）细胞显示有缺陷的钙库操作的Ca 2+进入（SOCE）和严重缺陷的细胞毒性颗粒胞吐作用，导致靶细胞溶解受损。使用来自基质相互作用分子1缺陷患者的NK细胞获得了类似的发现。该缺陷发生在信号传导过程的后期，因为白细胞功能抗原（LFA）-1和细胞毒性颗粒极化的活化没有受损。此外，SOCE的药理学抑制干扰了健康供体新鲜分离的NK细胞和CD 8（+）效应T细胞的脱粒和靶细胞溶解。除了对淋巴细胞细胞毒性的影响外，在ORAI 1缺陷型NK细胞中，趋化因子巨噬细胞炎性蛋白-1 β和细胞因子TNF-α和IFN-γ对靶细胞识别的合成受损，如先前对T细胞所述。相比之下，由IL-12、IL-15和IL-18的组合诱导的NK细胞细胞因子产生不受ORAI 1缺陷的损害。综上所述，这些结果确定了ORAI 1介导的Ca 2+内流在淋巴细胞细胞毒性的颗粒胞吐作用以及靶细胞识别诱导的细胞因子产生中的关键作用。
Lymphocytes mediate cytotoxicity by polarized release of the contents of cytotoxic granules toward their target cells. Here, we have studied the role of the calcium release-activated calcium channel ORAI1 in human lymphocyte cytotoxicity. Natural killer (NK) cells obtained from an ORAI1-deficient patient displayed defective store-operated Ca2+ entry (SOCE) and severely defective cytotoxic granule exocytosis leading to impaired target cell lysis. Similar findings were obtained using NK cells from a stromal interaction molecule 1-deficient patient. The defect occurred at a late stage of the signaling process, because activation of leukocyte functional antigen (LFA)-1 and cytotoxic granule polarization were not impaired. Moreover, pharmacological inhibition of SOCE interfered with degranulation and target cell lysis by freshly isolated NK cells and CD8(+) effector T cells from healthy donors. In addition to effects on lymphocyte cytotoxicity, synthesis of the chemokine macrophage inflammatory protein-1 beta and the cytokines TNF-alpha and IFN-gamma on target cell recognition was impaired in ORAI1-deficient NK cells, as previously described for T cells. By contrast, NK cell cytokine production induced by combinations of IL-12, IL-15, and IL-18 was not impaired by ORAI1 deficiency. Taken together, these results identify a critical role for ORAI1-mediated Ca2+ influx in granule exocytosis for lymphocyte cytotoxicity as well as for cytokine production induced by target cell recognition.