The critical role of protein kinase C-θ in Fas/Fas ligand-mediated apoptosis
The critical role of protein kinase C-θ in Fas/Fas ligand-mediated apoptosis
复制标题
DOI：
10.4049/jimmunol.178.1.312
复制
发表时间：
2007-01-01
影响因子：
4.4
通讯作者：
Sun, Zuoming
中科院分区：
文献类型：
--
作者：
Manicassainy, Santhakumar;Sun, Zuoming
功能性免疫系统不仅需要抗原特异性T细胞的快速扩增，而且需要克隆扩增的T细胞的有效缺失以避免T细胞的积累。Fas/Fas配体（FasL）介导的凋亡在活化的外周血T细胞的缺失中起关键作用，这清楚地通过超抗原诱导的扩增和随后的T细胞缺失来证明。在这项研究中，我们发现，在蛋白激酶C-θ（PKC-θ）的情况下，超抗原（葡萄球菌肠毒素B）诱导的V β 8（+）CD 4（+）T细胞缺失在PKC-θ（-/-）小鼠中是有缺陷的。在葡萄球菌肠毒素B攻击的反应中，在PKC-θ（-/-）小鼠中，FasL的上调而不是Fas的上调显著降低。因此，体内FasL的最大上调需要PKC-θ。我们进一步表明，FasL表达的刺激依赖于PKC-θ介导的NF-AT通路的激活。此外，PKC-θ（-/-）T细胞显示出对Fas介导的凋亡以及活化诱导的细胞死亡（AICD）的抗性。在没有PKC-θ的情况下，Fas诱导的凋亡分子如caspase-8、caspase-3和Bid的活化是无效的。然而，AICD以及Fas介导的PKC-θ（-/-）T细胞的凋亡在高浓度的IL-2的存在下恢复，IL-2是增强T细胞用于AICD所需的关键因子。因此，PKC-θ是促进FasL表达和增强Fas介导的细胞凋亡所必需的。
A functional immune system not only requires rapid expansion of antigenic specific T cells, but also requires efficient deletion of clonally expanded T cells to avoid accumulation of T cells. Fas/Fas ligand (FasL)-mediated apoptosis plays a critical role in the deletion of activated peripheral T cells, which is clearly demonstrated by superantigen-induced expansion and subsequent deletion of T cells. In this study, we show that in the absence of protein kinase C-theta (PKC-theta), superantigen (staphylococcal enterotoxin B)-induced deletion of V beta 8(+) CD4(+) T cells was defective in PKC-theta(-/-) mice. In response to staphylococcal enterotoxin B challenge, up-regulation of FasL, but not Fas, was significantly reduced in PKC-theta(-/-) mice. PKC-theta is thus required for maximum up-regulation of FasL in vivo. We further show that stimulation of FasL expression depends on PKC-theta-mediated activation of NF-AT pathway. In addition, PKC-theta(-/-) T cells displayed resistance to Fas-mediated apoptosis as well as activation-induced cell death (AICD). In the absence of PKC-theta, Fas-induced activation of apoptotic molecules such as caspase-8, caspase-3, and Bid was not efficient. However, AICD as well as Fas-mediated apoptosis of PKC-theta(-/-) T cells were restored in the presence of high concentration of IL-2, a critical factor required for potentiating T cells for AICD. PKC-theta is thus required for promoting FasL expression and for potentiating Fas-mediated apoptosis.