FOXP3 protects conventional human T cells from premature restimulation-induced cell death.
FOXP3 protects conventional human T cells from premature restimulation-induced cell death.
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FOXP3 保护传统人类 T 细胞免受再刺激引起的过早细胞死亡。
DOI：
10.1038/s41423-019-0316-z
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发表时间：
2021
影响因子：
24.1
通讯作者：
Snow,AndrewL
中科院分区：
文献类型：
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作者：
Voss,Kelsey;Lake,Camille;Luthers,ChristopherR;Lott,NathanielM;Dorjbal,Batsukh;Arjunaraja,Swadhinya;Bauman,BradlyM;Soltis,AnthonyR;Sukumar,Gauthaman;Dalgard,CliftonL;Snow,AndrewL
适应性免疫应答依赖于特定的凋亡程序来维持稳态。常规效应T细胞（Tcon）扩增受到叉头框P3（FOXP3）+调节性T细胞（Tcells）和再刺激诱导的细胞死亡（RICD）两者的限制，再刺激诱导的细胞死亡是由通过T细胞受体（TCR）的重复刺激触发的杀固有细胞凋亡途径。组成型FOXP3表达通过抑制SLAM相关蛋白（SAP）（一种放大TCR信号强度的关键衔接蛋白）来保护TCR免受RICD影响。暂时FOXP3诱导在活化的人CD4和CD8 Tcons中的作用尚未得到解决，但其表达与获得性RICD敏感性呈负相关。在这里，我们描述了一个新的作用FOXP3在保护人类Tcons从过早的RICD在扩张过程中。与Tcons中FOXP3介导的RICD保护不同，FOXP3通过需要从头转录的独特机制保护Tcons，而不需要SAP抑制。扩增Tcons的转录组分析和功能分析显示，FOXP3增强SLAM家族受体CD48的表达，这反过来又维持基础自噬并抑制促凋亡p53信号传导。在TCR再刺激后，CD48和FOXP3表达均减少p53积累。此外，沉默FOXP3表达或阻断CD48降低了扩展Tcons中的线粒体膜电位，同时减少了基础自噬。我们的研究结果表明，FOXP3在早期效应Tcons中控制着一个独特的转录程序，该程序通过CD48依赖性保护性自噬和p53抑制来维持RICD抗性。
The adaptive immune response relies on specific apoptotic programs to maintain homeostasis. Conventional effector T cell (Tcon) expansion is constrained by both forkhead box P3 (FOXP3)+-regulatory T cells (Tregs) and restimulation-induced cell death (RICD), a propriocidal apoptosis pathway triggered by repeated stimulation through the T-cell receptor (TCR). Constitutive FOXP3 expression protects Tregs from RICD by suppressing SLAM-associated protein (SAP), a key adaptor protein that amplifies TCR signaling strength. The role of transient FOXP3 induction in activated human CD4 and CD8 Tcons remains unresolved, but its expression is inversely correlated with acquired RICD sensitivity. Here, we describe a novel role for FOXP3 in protecting human Tcons from premature RICD during expansion. Unlike FOXP3-mediated protection from RICD in Tregs, FOXP3 protects Tcons through a distinct mechanism requiring de novo transcription that does not require SAP suppression. Transcriptome profiling and functional analyses of expanding Tcons revealed that FOXP3 enhances expression of the SLAM family receptor CD48, which in turn sustains basal autophagy and suppresses pro-apoptotic p53 signaling. Both CD48 and FOXP3 expression reduced p53 accumulation upon TCR restimulation. Furthermore, silencing FOXP3 expression or blocking CD48 decreased the mitochondrial membrane potential in expanding Tcons with a concomitant reduction in basal autophagy. Our findings suggest that FOXP3 governs a distinct transcriptional program in early-stage effector Tcons that maintains RICD resistance via CD48-dependent protective autophagy and p53 suppression.