Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Immunology, Hubei University of Medicine, Shiyan, China.
FASEB J. 2021 Jan;35(1):e21138. doi: 10.1096/fj.201903067RR. Epub 2020 Nov 13.
Appropriate migration of cytotoxic T effector cells into the tumors is crucial for their antitumor function. Despite the controversial role of PI3K-Akt in CD8 T cell mTORC1 activation, a link between Akt-mTORC1 signaling and CD8 trafficking has been demonstrated. We have recently discovered that TCR-induced calcineurin activates DAPK1, which interacts with TSC2 via its death domain and phosphorylates TSC2 via its kinase domain to mediate mTORC1 activation in CD8 T cells. However, whether DAPK1 regulates CD8 trafficking into tumors remains unclear. Here, using pharmacological inhibitor and genetic approaches, we found that like rapamycin, inhibition of DAPK1 activity led to enhanced expression of the homing receptors CD62L and CCR7. Deletion of either kinase domain or death domain in the T cell compartment reduced the T cell activation and maintained the expression of CD62L and CCR7. DAPK1-DD-deficient mice were more susceptible to tumor growth and deficiency of DAPK1 activity significantly reduced the migratory ability of CD8 into the tumors. These data revealed a crucial role of DAPK1-mTORC1 in mediating CD8 trafficking and antitumor function.
细胞毒性 T 效应细胞（Cytotoxic T effector cells）适当地迁移到肿瘤中对其抗肿瘤功能至关重要。尽管 PI3K-Akt 在 CD8 T 细胞 mTORC1 激活中的作用存在争议，但 Akt-mTORC1 信号通路与 CD8 细胞迁移之间存在联系已得到证实。我们最近发现，TCR 诱导的钙调神经磷酸酶激活了 DAPK1，后者通过其死亡结构域与 TSC2 相互作用，并通过其激酶结构域磷酸化 TSC2，从而介导 CD8 T 细胞中 mTORC1 的激活。然而，DAPK1 是否调节 CD8 细胞向肿瘤的迁移仍不清楚。在这里，我们使用药理学抑制剂和遗传方法发现，与雷帕霉素一样，抑制 DAPK1 活性导致归巢受体 CD62L 和 CCR7 的表达增强。在 T 细胞区室中敲除激酶结构域或死亡结构域会降低 T 细胞的激活，并维持 CD62L 和 CCR7 的表达。DAPK1-DD 缺陷型小鼠对肿瘤生长更敏感，而 DAPK1 活性的缺失则显著降低了 CD8 向肿瘤的迁移能力。这些数据揭示了 DAPK1-mTORC1 在介导 CD8 细胞迁移和抗肿瘤功能中的关键作用。
