TBK1 和 IKKε 通过炎症凋亡机制保护靶细胞免受 IFNγ 介导的 T 细胞杀伤

bioRxiv Pub Date : 2024-08-08 DOI:10.1101/2024.08.06.606693
Nicholas D. Sun, Allison R. Carr, Erica N. Krogman, Yogesh Chawla, Jun Zhong, Matthew C. Guttormson, Mark Chan, Michelle A. Hsu, Haidong Dong, D. Bogunovic, Akhilesh Pandey, Laura M. Rogers, Adrian T. Ting
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引用次数: 0

摘要

细胞毒性 T 细胞能产生干扰素γ(IFNγ),它在抗微生物和抗肿瘤反应中起着至关重要的作用。然而,T 细胞衍生的 IFNγ 是否能直接杀死感染细胞和肿瘤靶细胞,以及如何对其进行调控,目前尚不清楚。在这里,我们报告了靶细胞表达的激酶 TBK1 和 IKKε 通过抑制 T 细胞衍生的 IFNγ 杀死靶细胞的能力来调节 IFNγ 的细胞毒性。在缺乏 TBK1 和 IKKε 的肿瘤靶细胞中,IFNγ 会诱导 TNFR1 和 Z 核酸传感器 ZBP1 的表达,从而引发 RIPK1 依赖性细胞凋亡,这主要是以靶细胞自主的方式进行的。出乎意料的是,已知不会向 NFκB 发出信号的 IFNγ 在 TBK1 和 IKKε 双缺陷细胞中诱导 NFκB 过度激活。TBK1 和 IKKε 可抑制 IKKα/β 的活性,在它们缺失的情况下,IFNγ 会诱导 NFκB 依赖性炎症趋化因子和细胞因子的表达升高。细胞凋亡被认为是非炎症性的,但我们的观察结果表明,IFNγ 能诱导炎症形式的细胞凋亡,而这种凋亡受到 TBK1 和 IKKε 的抑制。这两种激酶通过调节以下三种关键反应,在先天性免疫反应和适应性免疫反应之间建立了关键的联系:(1)IRF3/7 的磷酸化以诱导 IFN 型;(2)抑制 RIPK1 依赖性死亡;以及(3)抑制 NFκB 依赖性炎症。我们认为,这些激酶进化出了这些功能,因此病原体试图阻断 IFN 表达时对它们的抑制将使 IFNγ 能够触发凋亡,并伴随着另一种炎症反应。我们的研究结果表明,靶细胞中 TBK1 和 IKKε 的缺失会使它们对 T 细胞衍生的 IFNγ 诱导的炎症性凋亡敏感。简短摘要 在缺乏 TBK1 和 IKKε 的情况下,靶细胞会以 IFNγ 依赖性方式被 T 细胞杀死。在缺乏 TBK1 和 IKKε 的细胞中,IFNγ 会诱导 RIPK1 依赖性死亡,并过度诱导 NFκB 依赖性炎症基因。这表明,任何抑制 TBK1/IKKε 以阻断 IFN 表达的行为都会导致细胞死亡,并伴随着另一种炎症程序。图表摘要
本文章由计算机程序翻译,如有差异,请以英文原文为准。
TBK1 and IKKε protect target cells from IFNγ-mediated T cell killing via an inflammatory apoptotic mechanism
Cytotoxic T cells produce interferon gamma (IFNγ), which plays a critical role in anti-microbial and anti-tumor responses. However, it is not clear whether T cell-derived IFNγ directly kills infected and tumor target cells, and how this may be regulated. Here, we report that target cell expression of the kinases TBK1 and IKKε regulate IFNγ cytotoxicity by suppressing the ability of T cell-derived IFNγ to kill target cells. In tumor targets lacking TBK1 and IKKε, IFNγ induces expression of TNFR1 and the Z-nucleic acid sensor, ZBP1, to trigger RIPK1-dependent apoptosis, largely in a target cell-autonomous manner. Unexpectedly, IFNγ, which is not known to signal to NFκB, induces hyperactivation of NFκB in TBK1 and IKKε double-deficient cells. TBK1 and IKKε suppress IKKα/β activity and in their absence, IFNγ induces elevated NFκB-dependent expression of inflammatory chemokines and cytokines. Apoptosis is thought to be non-inflammatory, but our observations demonstrate that IFNγ can induce an inflammatory form of apoptosis, and this is suppressed by TBK1 and IKKε. The two kinases provide a critical connection between innate and adaptive immunological responses by regulating three key responses: (1) phosphorylation of IRF3/7 to induce type I IFN; (2) inhibition of RIPK1-dependent death; and (3) inhibition of NFκB-dependent inflammation. We propose that these kinases evolved these functions such that their inhibition by pathogens attempting to block type I IFN expression would enable IFNγ to trigger apoptosis accompanied by an alternative inflammatory response. Our findings show that loss of TBK1 and IKKε in target cells sensitizes them to inflammatory apoptosis induced by T cell-derived IFNγ. Short Summary In the absence of TBK1 and IKKε, target cells are killed by T cells in an IFNγ-dependent manner. In TBK1 and IKKε-deficient cells, IFNγ induces RIPK1-dependent death, as well as hyper-induction of NFκB-dependent inflammatory genes. This suggests that any inhibition of TBK1/IKKε to block type I IFN expression will result in the demise of the cell accompanied by an alternate inflammatory program. Graphical Abstract
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