IL-6 and TNFα Drive Extensive Proliferation of Human Tregs Without Compromising Their Lineage Stability or Function.
IL-6 and TNFα Drive Extensive Proliferation of Human Tregs Without Compromising Their Lineage Stability or Function.
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DOI：
10.3389/fimmu.2021.783282
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发表时间：
2021
影响因子：
7.3
通讯作者：
Tang Q
中科院分区：
文献类型：
--
作者：
Skartsis N;Peng Y;Ferreira LMR;Nguyen V;Ronin E;Muller YD;Vincenti F;Tang Q
Treg疗法正在移植和自身免疫性疾病的临床试验中进行测试，然而，炎症对Treg的影响仍然存在争议。我们用促炎细胞因子IL-6和TNFα离体激发人T细胞，并观察到抗CD 3和抗CD 28（aCD 3/28）珠或CD 28超激动剂（CD 28 SA）刺激的增殖显著增强。暴露于苦参碱的TcR维持FOXP 3和HELIOS、去甲基化FOXP 3增强子的高表达，以及低IFNγ、IL-4和IL-17分泌。使用依那西普阻断TNF受体或使用CRISPR/Cas9缺失TNF受体2减弱了Treg增殖并减弱了FOXP 3和HELIOS表达。这些结果促使我们考虑将CD 28 SA与IL-6和TNFα一起使用，而不使用aCD 3/28珠粒（无珠粒）作为治疗性Treg生产的替代方案。代谢组学分析显示，在无珠Treg扩增过程中，糖酵解和氧化磷酸化更活跃，能量产生增加，抗氧化潜力更高。最后，无珠扩增的THBE在体外和体内保持抑制功能。这些结果表明，人TcR对促炎细胞因子有积极的反应，具有增强的增殖，而不损害其谱系身份或功能。这种性质可以用于治疗性Treg制造。
Treg therapies are being tested in clinical trials in transplantation and autoimmune diseases, however, the impact of inflammation on Tregs remains controversial. We challenged human Tregs ex-vivo with pro-inflammatory cytokines IL-6 and TNFα and observed greatly enhanced proliferation stimulated by anti-CD3 and anti-CD28 (aCD3/28) beads or CD28 superagonist (CD28SA). The cytokine-exposed Tregs maintained high expression of FOXP3 and HELIOS, demethylated FOXP3 enhancer, and low IFNγ, IL-4, and IL-17 secretion. Blocking TNF receptor using etanercept or deletion of TNF receptor 2 using CRISPR/Cas9 blunted Treg proliferation and attenuated FOXP3 and HELIOS expression. These results prompted us to consider using CD28SA together with IL-6 and TNFα without aCD3/28 beads (beadless) as an alternative protocol for therapeutic Treg manufacturing. Metabolomics profiling revealed more active glycolysis and oxidative phosphorylation, increased energy production, and higher antioxidant potential during beadless Treg expansion. Finally, beadless expanded Tregs maintained suppressive functions in vitro and in vivo. These results demonstrate that human Tregs positively respond to proinflammatory cytokines with enhanced proliferation without compromising their lineage identity or function. This property can be harnessed for therapeutic Treg manufacturing.
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影响因子：
5.4
作者：
Chen, Xin;Subleski, Jeffrey J.;Hamano, Ryoko;Howard, O. M. Zack;Wiltrout, Robert H.;Oppenheim, Joost J.
通讯作者：
Oppenheim, Joost J.
影响因子：
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作者：
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作者：
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Steinmetz, Oliver M.
影响因子：
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作者：
de Kivit, Sander;Mensink, Mark;Borst, Jannie
通讯作者：
Borst, Jannie
影响因子：
29
作者：
Angelin A;Gil-de-Gómez L;Dahiya S;Jiao J;Guo L;Levine MH;Wang Z;Quinn WJ 3rd;Kopinski PK;Wang L;Akimova T;Liu Y;Bhatti TR;Han R;Laskin BL;Baur JA;Blair IA;Wallace DC;Hancock WW;Beier UH
通讯作者：
Beier UH