Regulation of NKG2D+CD8+ T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism
Regulation of NKG2D+CD8+ T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism
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DOI：
10.1080/2162402x.2016.1252012
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Li, Shulin
中科院分区：
文献类型：
--
作者：
Hu, Jiemiao;Batth, Izhar S.;Li, Shulin
自然杀伤（NK）组2D （NKG2D）受体，显示在小鼠和人类NK细胞上，激活CD8(+) T细胞和其他T细胞的小亚群。NKG2D(+)CD8(+) T细胞在先天免疫和适应性免疫中发挥关键作用，通过与NKG2D配体结合消除肿瘤和感染细胞。尽管NKG2D(+)CD8(+) T细胞在免疫监视中发挥重要作用，但如何调节NKG2D在CD8(+) T细胞上的表达的机制仍然不清楚。我们用CD80重组蛋白处理小鼠和人CD8(+)T细胞，再加上一个带有小分子抑制剂的药理学模型，以确定哪种信号通路导致NKG2D对CD8(+)T细胞的调节。本研究表明，CD28激活以信号转换器和转录激活因子3 （STAT3）磷酸化依赖的方式在小鼠和人CD8(+) T细胞上引起持续的NKG2D表达。此外，我们发现CD28激活刺激酪氨酸激酶Lck的持续激活，酪氨酸激酶Lck招募并触发Janus激酶/STAT3信号使STAT3磷酸化，进而增加NKG2D的表达。此外，NKG2D诱导CD8(+) T细胞在体外对靶肿瘤细胞具有细胞溶解活性，并以NKG2D依赖的方式显著提高体内抗肿瘤治疗效果。综上所述，这些结果阐明了CD28激活后磷酸化的STAT3 （pSTAT3）对CD8(+) T细胞调控NKG2D的新机制。这一机制可能揭示了基于cd80、依赖nkg2d的抗肿瘤免疫治疗的有效性。
The natural killer (NK) group 2D (NKG2D) receptor, which displays on mouse and human NK cells, activates CD8(+) T cells and small subsets of other T cells. NKG2D(+)CD8(+) T cells play critical roles in both innate and adaptive immunity upon engagement with NKG2D ligands to eliminate tumor and infected cells. Despite the important role of NKG2D(+)CD8(+) T cells in immune surveillance, the mechanisms of how NKG2D expression on CD8(+) T cells is regulated remain poorly defined. We treated mouse and human CD8(+) T cells with CD80 recombinant protein, plus a pharmacologic model with small molecular inhibitors to determine which signaling pathway leads to NKG2D regulation on CD8(+)T cells. This study revealed that CD28 activation gives rise to sustained NKG2D expression on both mouse and human CD8(+) T cells in a signal transducer and activator of transcription 3 (STAT3) phosphorylation-dependent manner. Further, we found that CD28 activation stimulated sustained activation of the tyrosine kinase Lck, which recruits and triggers Janus kinase/STAT3 signaling to phosphorylate STAT3, and in turn increases NKG2D expression. Moreover, NKG2D induction on CD8(+) T cells exerts cytolytic activity against target tumor cells in vitro, as well as significantly improves the antitumor therapeutic effects in vivo in an NKG2D-dependent manner. Taken together, these results elucidated a novel mechanism of NKG2D regulation by phosphorylated STAT3 (pSTAT3) on CD8(+) T cells upon CD28 activation. This mechanism may shed light on the effectiveness of CD80-based, NKG2D-dependent antitumor immunotherapy.