Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
J Immunol. 2011 Jan 15;186(2):931-9. doi: 10.4049/jimmunol.1001092. Epub 2010 Dec 15.
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-κB pathway. TRAIL induced the NF-κB pathway by phosphorylation of inhibitor of κB factor kinase and protein kinase C 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-κB 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. These results demonstrate that TRAIL costimulation mediates NF-κB 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-κB-dependent signals from the TCR and TRAIL in T lymphocytes.
肿瘤坏死因子相关凋亡诱导配体（TNF-related apoptosis-inducing ligand，TRAIL）被证明能提供共刺激信号，与 TCR/CD3 复合物协同诱导 T 细胞增殖和细胞因子产生。尽管许多信号通路与 TCR/CD3 复合物有关，但尚不清楚这两个受体如何合作诱导 T 细胞活化。在这项研究中，我们表明 TRAIL 诱导的 T 细胞共刺激依赖于 NF-κB 途径的激活。TRAIL 通过与抗 CD3 联合作用，磷酸化 IκB 激酶和蛋白激酶 C 诱导 NF-κB 途径。此外，我们证明 TRAIL 共刺激诱导 TCR 近端上游酪氨酸激酶 Lck 和 ZAP70 的磷酸化。可溶性受体 DR4-Fc 单独结合 TRAIL 能够诱导 Lck 和 ZAP70 的磷酸化，并激活 NF-κB 途径；然而，它不足以完全激活 T 细胞以支持 T 细胞增殖。相比之下，TRAIL 与抗 CD3 的结合，而不是 TRAIL 的单独结合，诱导脂筏组装和 Lck 和 PKC 的募集。这些结果表明，TRAIL 共刺激通过脂筏组装和 Lck 的募集来介导 NF-κB 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 TCR 和 TRAIL 的有丝分裂 NF-κB 依赖性信号，在 T 淋巴细胞中。
