Protein kinase Cδ regulates antigen receptor-induced lytic granule polarization in mouse CD8+ CTL
Protein kinase Cδ regulates antigen receptor-induced lytic granule polarization in mouse CD8+ CTL
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DOI：
10.4049/jimmunol.178.12.7814
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发表时间：
2007-06-15
影响因子：
4.4
通讯作者：
Radoja, Sasa
中科院分区：
文献类型：
--
作者：
Ma, Jennifer S. Y.;Monu, Ngozi;Radoja, Sasa
裂解颗粒胞吐作用是CD8(+) CTL杀死病毒感染细胞和肿瘤细胞的主要途径。尽管该途径在适应性 T 细胞免疫中具有明显的重要性，但参与调节该过程的酶的分子特性却很少被表征。已知对调节 CD8+ T 细胞中颗粒胞吐作用介导的细胞毒性至关重要的一种信号是 Ag 受体诱导的蛋白激酶 C (PKC) 激活。然而，尚不清楚该过程的哪一步是由 PKC 监管的。此外，迄今为止尚未确定哪些 PKC 家族成员是调节溶解颗粒胞吐作用所必需的。通过结合药物抑制剂和使用具有靶向基因删除的小鼠，我们表明 PKC δ 是小鼠 CD8(+) T 细胞中颗粒胞吐作用介导的裂解功能所必需的。我们的研究表明，PKC δ 是裂解颗粒胞吐作用所必需的，但对于响应 TCR 刺激的激活、细胞因子产生和溶细胞分子的表达而言，PKC δ 是可有可无的。重要的是，PKC δ 缺陷的细胞毒性淋巴细胞中的裂解功能缺陷可通过 PKC δ 的异位表达来逆转。最后，我们表明 PKC δ 不参与靶细胞诱导的微管组织中心的重新定向，但是后续胞吐步骤（即裂解颗粒极化）所必需的。因此，我们的研究将 PKC δ 确定为小鼠 CD8+ T 细胞中 Ag 受体诱导的溶解颗粒极化的新型选择性调节剂。
Lytic granule exocytosis is the major pathway used by CD8(+) CTL to kill virally infected and tumor cells. Despite the obvious importance, of this pathway in adaptive T cell immunity, the molecular identity of enzymes involved in the regulation of this process is poorly characterized. One signal known to be critical for the regulation of granule exocytosis-mediated cytotoxicity in CD8+ T cells is Ag receptor-induced activation of protein kinase C (PKC). However, it is not known which step of the process is regulated by PKC. In addition, it has not been determined to date which of the PKC family members is required for the regulation of lytic granule exocytosis. By combination of pharmacological inhibitors and use of mice with targeted gene deletions, we show that PKC delta is required for granule exocytosis-mediated lytic function in mouse CD8(+) T cells. Our studies demonstrate that PKC delta is required for lytic granule exocytosis, but is dispensable for activation, cytokine production, and expression of cytolytic molecules in response to TCR stimulation. Importantly, defective lytic function in PKC delta-deficient cytotoxic lymphocytes is reversed by ectopic expression of PKC delta. Finally, we show that PKC delta is not involved in target cell-induced reorientation of the microtubule-organizing center, but is required for the subsequent exocytosis step, i.e., lytic granule polarization. Thus, our studies identify PKC delta as a novel and selective regulator of Ag receptor-induced lytic granule polarization in mouse CD8+ T cells.