T cell-derived tumor necrosis factor induces cytotoxicity by activating RIPK1-dependent target cell death.
T cell-derived tumor necrosis factor induces cytotoxicity by activating RIPK1-dependent target cell death.
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DOI：
10.1172/jci.insight.148643
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发表时间：
2021-12-22
期刊：
影响因子：
8
通讯作者：
Ting AT
中科院分区：
文献类型：
--
作者：
Chun N;Ang RL;Chan M;Fairchild RL;Baldwin WM 3rd;Horwitz JK;Gelles JD;Chipuk JE;Kelliher MA;Pavlov VI;Li Y;Homann D;Heeger PS;Ting AT
肿瘤坏死因子受体1的肿瘤坏死因子受体1通过以下途径促进炎症和细胞存活：(A)抑制RIPK1的S死亡信号功能，激活NF-κB；或(B)使RIPK1与死亡诱导信号复合体结合，启动细胞凋亡或坏死下垂。导致RIPK1依赖的细胞死亡的肿瘤坏死因子的细胞来源尚不清楚。为了解决这一问题，我们采用了依赖T细胞的移植或肿瘤排斥反应的体外系统和小鼠模型，在这些模型中，靶细胞对依赖RIPK1的细胞死亡的敏感性可以被基因改变。我们证明，T细胞释放的肿瘤坏死因子是激活靶细胞中依赖RIPK1的细胞死亡的必要条件和充分条件，从而不依赖于T细胞频率而介导靶细胞杀伤。T细胞来源的肿瘤坏死因子激活靶细胞中依赖RIPK1的细胞死亡程序，加速小鼠心脏移植排斥反应，并与抗PD1注射协同作用，摧毁具有检查点阻断抗性的小鼠黑色素瘤。总之，这些发现揭示了细胞毒效应T细胞与其抗原靶标发生同源相互作用后释放的肿瘤坏死因子在免疫学上的独特作用。操纵T细胞肿瘤坏死因子和/或靶细胞对依赖RIPK1的细胞死亡的易感性可以被用来减轻或增强对同种异体移植物和恶性肿瘤的T细胞依赖的破坏，以改善预后。
TNF ligation of TNF receptor 1 (TNFR1) promotes either inflammation and cell survival by (a) inhibiting RIPK1’s death-signaling function and activating NF-κB or (b) causing RIPK1 to associate with the death-inducing signaling complex to initiate apoptosis or necroptosis. The cellular source of TNF that results in RIPK1-dependent cell death remains unclear. To address this, we employed in vitro systems and murine models of T cell–dependent transplant or tumor rejection in which target cell susceptibility to RIPK1-dependent cell death could be genetically altered. We show that TNF released by T cells is necessary and sufficient to activate RIPK1-dependent cell death in target cells and thereby mediate target cell cytolysis independently of T cell frequency. Activation of the RIPK1-dependent cell death program in target cells by T cell–derived TNF accelerates murine cardiac allograft rejection and synergizes with anti-PD1 administration to destroy checkpoint blockade–resistant murine melanoma. Together, the findings uncover a distinct immunological role for TNF released by cytotoxic effector T cells following cognate interactions with their antigenic targets. Manipulating T cell TNF and/or target cell susceptibility to RIPK1-dependent cell death can be exploited to either mitigate or augment T cell–dependent destruction of allografts and malignancies to improve outcomes.
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DOI：
10.4049/jimmunol.1302729
发表时间：
2014-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
DeBerge MP;Ely KH;Enelow RI
通讯作者：
Enelow RI
影响因子：
8.7
作者：
Boyle, JJ;Bowyer, DE;Bennett, MR
通讯作者：
Bennett, MR
影响因子：
16
作者：
Bertrand, Mathieu J. M.;Milutinovic, Snezana;Barker, Philip A.
通讯作者：
Barker, Philip A.
影响因子：
8.8
作者：
Gan, Ingrid;Jiang, Jifu;Zhang, Zhu-Xu
通讯作者：
Zhang, Zhu-Xu
影响因子：
4.6
作者：
Allie, Nasiema;Grivennikov, Sergei I.;Keeton, Roanne;Hsu, Nai-Jen;Bourigault, Marie-Laure;Court, Nathalie;Fremond, Cecile;Yeremeev, Vladimir;Shebzukhov, Yuriy;Ryffel, Bernhard;Nedospasov, Sergei A.;Quesniaux, Valerie F. J.;Jacobs, Muazzam
通讯作者：
Jacobs, Muazzam