Attenuation of canonical NF-κB signaling maintains function and stability of human Treg.
Attenuation of canonical NF-κB signaling maintains function and stability of human Treg.
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DOI：
10.1111/febs.15361
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Schmetterer KG
中科院分区：
文献类型：
--
作者：
Ziegler LS;Gerner MC;Schmidt RLJ;Trapin D;Steinberger P;Pickl WF;Sillaber C;Egger G;Schwarzinger I;Schmetterer KG
活化B细胞的核因子“κ -轻链增强子”（NF - κB）信号通路是大多数免疫细胞用于促进免疫刺激功能的信号通路。最近的研究表明，调节性T细胞（Treg）差异整合TCR来源的信号，从而维持其抑制特征。然而，NF - κB信号在人外周血（PB） Treg活化中的作用迄今尚未完全阐明。我们发现主转录因子叉头盒蛋白3 （FOXP3）的活性减弱了人类Treg中NF - κB蛋白p50、p65和c - Rel的p65磷酸化和核易位。通过对FOXP3转基因T细胞和来自健康供体的PB Treg以及来自原发性NFKB1单倍不全患者的Treg的典型NF - κB信号的药理学和遗传学抑制，我们验证了Treg的激活和抑制能力独立于NF - κB信号。此外，抑制Treg中残留的NF - κB信号进一步增强白细胞介素- 10 （IL - 10）的产生。阻断NF‐κB信号传导可用于体外诱导Treg （iTreg）的生成，具有增强的抑制能力和功能稳定性。在这方面，与单独阻断mTOR产生的iTreg相比，双重阻断哺乳动物雷帕霉素靶蛋白（mTOR）和NF - κB信号传导，伴随着转录因子FOXP1和FOXP3的表达增强以及Treg特异性去甲基化区域的去甲基化。因此，我们首次深入了解了NF - κB信号在人类Treg中的作用。这些发现可能导致选择性操纵Treg和生成用于细胞治疗的改良iTreg的策略。与效应T细胞相比，人类调节性T细胞（Treg）整合细胞外信号（如mTOR、MAP激酶和JAK/STAT信号）的方式存在差异。在这项研究中，Ziegler等人首次表明Treg也能减弱TCR触发的典型NF - κB信号。这种独特的特性也可以用于诱导Treg的生成。mTOR和NF - κB联合阻断可诱导Treg，抑制能力增强，功能稳定性改善。
Nuclear factor ‘κ‐light‐chain‐enhancer’ of activated B cells (NF‐κB) signaling is a signaling pathway used by most immune cells to promote immunostimulatory functions. Recent studies have indicated that regulatory T cells (Treg) differentially integrate TCR‐derived signals, thereby maintaining their suppressive features. However, the role of NF‐κB signaling in the activation of human peripheral blood (PB) Treg has not been fully elucidated so far. We show that the activity of the master transcription factor forkhead box protein 3 (FOXP3) attenuates p65 phosphorylation and nuclear translocation of the NF‐κB proteins p50, p65, and c‐Rel following activation in human Treg. Using pharmacological and genetic inhibition of canonical NF‐κB signaling in FOXP3‐transgenic T cells and PB Treg from healthy donors as well as Treg from a patient with a primary NFKB1 haploinsufficiency, we validate that Treg activation and suppressive capacity is independent of NF‐κB signaling. Additionally, repression of residual NF‐κB signaling in Treg further enhances interleukin‐10 (IL‐10) production. Blockade of NF‐κB signaling can be exploited for the generation of in vitro induced Treg (iTreg) with enhanced suppressive capacity and functional stability. In this respect, dual blockade of mammalian target of rapamycin (mTOR) and NF‐κB signaling was accompanied by enhanced expression of the transcription factors FOXP1 and FOXP3 and demethylation of the Treg‐specific demethylated region compared to iTreg generated under mTOR blockade alone. Thus, we provide first insights into the role of NF‐κB signaling in human Treg. These findings could lead to strategies for the selective manipulation of Treg and the generation of improved iTreg for cellular therapy. Human regulatory T cells (Treg) differentially integrate extracellular signals (e.g., mTOR, MAP‐kinase, and JAK/STAT signaling) compared to effector T cells. In this work, Ziegler et al. for the first time show that Treg also attenuate TCR‐triggered canonical NF‐κB signaling. This unique feature can also be exploited for the generation of inducible Treg. Combination of mTOR and NF‐κB blockade leads to the induction of Treg with increased suppressive capacity and improved functional stability.
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影响因子：
14.9
作者：
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通讯作者：
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通讯作者：
Sun, Shao-Cong
视黄酸和雷帕霉素的单一作用和联合作用可调节诱导性人类调节性 T 细胞的生成、活性和归巢潜力。
影响因子：
3.7
作者：
Candia E;Reyes P;Covian C;Rodriguez F;Wainstein N;Morales J;Mosso C;Rosemblatt M;Fierro JA
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Fierro JA
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15.3
作者：
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