Helios, and not FoxP3, is the marker of activated Tregs expressing GARP/LAP.
Helios, and not FoxP3, is the marker of activated Tregs expressing GARP/LAP.
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DOI：
10.18632/oncotarget.4771
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发表时间：
2015-08-21
期刊：
影响因子：
--
通讯作者：
Chaudhary B
中科院分区：
文献类型：
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作者：
Elkord E;Abd Al Samid M;Chaudhary B
调节性T细胞（Tcells）是生理和病理生理环境中免疫调节/失调的关键参与者。尽管在了解Treg功能方面取得了重大进展，但仍然迫切需要定义可以区分不同Treg亚群的可靠和特异性标记物。在此，我们首次表明，活化Treg的标志物[潜伏相关肽（LAP）和糖蛋白A重复占主导地位（GARP或LRRC 32）]在稳定状态下表达Helios（FoxP 3-Helios+）的CD 4 + FoxP 3-T细胞上表达。在TCR活化后，GARP/CD 4 +Helios+ T细胞上调，而不管FoxP 3表达如何（FoxP 3 +/−Helios+）。我们发现，CD 4 +GARP+/− T细胞因子产生IL-10免疫抑制细胞因子，但不产生IFN-γ效应细胞因子。FoxP 3/Helios亚群的进一步表征显示，FoxP 3 +Helios+ Tcl 3在TCR刺激后的体外增殖显著低于FoxP 3 +Helios− Tcl 3。与FoxP 3 +Helios− Tcells不同，FoxP 3 +Helios+ Tcells分泌IL-10，但不分泌IFN-γ或IL-2，证实它们是具有免疫抑制特性的真正的Tcells。总的来说，Helios而不是FoxP 3是表达GARP/GARP的活化TcR的标志物，与FoxP 3 + Helios − TcR相比，FoxP 3 + Helios + TcR具有更多的抑制特性。我们的工作意味着，治疗自身免疫性和炎症性疾病、过敏和移植排斥的治疗方式应该被设计成诱导和/或扩增FoxP 3 +Helios+ TcR，而针对癌症或传染病的治疗应该避免这种扩增/诱导。
Regulatory T cells (Tregs) are key players of immune regulation/dysregulation both in physiological and pathophysiological settings. Despite significant advances in understanding Treg function, there is still a pressing need to define reliable and specific markers that can distinguish different Treg subpopulations. Herein we show for the first time that markers of activated Tregs [latency associated peptide (LAP) and glycoprotein A repetitions predominant (GARP, or LRRC32)] are expressed on CD4+FoxP3− T cells expressing Helios (FoxP3−Helios+) in the steady state. Following TCR activation, GARP/LAP are up-regulated on CD4+Helios+ T cells regardless of FoxP3 expression (FoxP3+/−Helios+). We show that CD4+GARP+/−LAP+ Tregs make IL-10 immunosuppressive cytokine but not IFN-γ effector cytokine. Further characterization of FoxP3/Helios subpopulations showed that FoxP3+Helios+ Tregs proliferate in vitro significantly less than FoxP3+Helios− Tregs upon TCR stimulation. Unlike FoxP3+Helios− Tregs, FoxP3+Helios+ Tregs secrete IL-10 but not IFN-γ or IL-2, confirming they are bona fide Tregs with immunosuppressive characteristics. Taken together, Helios, and not FoxP3, is the marker of activated Tregs expressing GARP/LAP, and FoxP3+Helios+ Tregs have more suppressive characteristics, compared with FoxP3+Helios− Tregs. Our work implies that therapeutic modalities for treating autoimmune and inflammatory diseases, allergies and graft rejection should be designed to induce and/or expand FoxP3+Helios+ Tregs, while therapies against cancers or infectious diseases should avoid such expansion/induction.