Lipid Raft Assembly and Lck Recruitment in TRAIL Costimulation Mediates NF-κB Activation and T Cell Proliferation
Lipid Raft Assembly and Lck Recruitment in TRAIL Costimulation Mediates NF-κB Activation and T Cell Proliferation
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DOI：
10.4049/jimmunol.1001092
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发表时间：
2011-01-15
影响因子：
4.4
通讯作者：
Hsu, Ping-Ning
中科院分区：
文献类型：
--
作者：
Huang, Shih-Chia;Tsai, Hwei-Fang;Hsu, Ping-Ning
TNF 相关的凋亡诱导配体可提供共刺激信号，与 TCR/CD3 复合物配合诱导 T 细胞增殖和细胞因子产生。尽管许多信号通路与 TCR/CD3 复合物相关，但尚不清楚这两种受体如何合作诱导 T 细胞激活。在这项研究中，我们表明 TRAIL 诱导的 T 细胞共刺激取决于 NF-kappa B 通路的激活。 TRAIL 通过 kappa B 因子激酶和蛋白激酶 C theta 抑制剂与抗 CD3 的磷酸化来诱导 NF-kappa B 通路。此外，我们证明 TRAIL 共刺激诱导上游 TCR 近端酪氨酸激酶 Lck 和 ZAP70 的磷酸化。 TRAIL 与其可溶性受体 DR4-Fc 的连接能够单独诱导 Lck 和 ZAP70 磷酸化并激活 NF-kappa B 通路；然而，它不足以完全激活T细胞以支持T细胞增殖。相反，TRAIL 与抗 CD3 结合，而不是单独的 TRAIL 连接，诱导脂筏组装和 Lck 和 PKC theta 的募集。这些结果表明，TRAIL 共刺激通过脂筏组装和 Lck 募集介导 NF-κ B 激活和 T 细胞增殖。我们的结果表明，在 TRAIL 共刺激中，Lck 的脂筏募集整合了来自 T 淋巴细胞中 TCR 和 TRAIL 的促有丝分裂 NF-κ B 依赖性信号。免疫学杂志，2011，186：931-939。
The TNF-related apoptosis-inducing ligand was shown to provide a costimulatory signal that cooperates with the TCR/CD3 complex to induce T cell proliferation and cytokine production. Although a number of signaling pathways were linked to the TCR/CD3 complex, it is not known how these two receptors cooperate to induce T cell activation. In this study, we show that TRAIL-induced costimulation of T cells depends on activation of the NF-kappa B pathway. TRAIL induced the NF-kappa B pathway by phosphorylation of inhibitor of kappa B factor kinase and protein kinase C theta in conjunction with anti-CD3. Furthermore, we demonstrated that TRAIL costimulation induced phosphorylation of the upstream TCR-proximal tyrosine kinases, Lck and ZAP70. Ligation of the TRAIL by its soluble receptor, DR4-Fc, alone was able to induce the phosphorylation of Lck and ZAP70 and to activate the NF-kappa B pathway; however, it was insufficient to fully activate T cells to support T cell proliferation. In contrast, TRAIL engagement in conjunction with anti-CD3, but not TRAIL ligation alone, induced lipid raft assembly and recruitment of Lck and PKC theta. These results demonstrate that TRAIL costimulation mediates NF-kappa B activation and T cell proliferation by lipid raft assembly and recruitment of Lck. Our results suggest that in TRAIL costimulation, lipid raft recruitment of Lck integrates mitogenic NF-kappa B-dependent signals from the TCR and TRAIL in T lymphocytes. The Journal of Immunology, 2011, 186: 931-939.