Interferon-alpha regulates the dynamic balance between human activated regulatory and effector T cells: implications for antiviral and autoimmune responses
Interferon-alpha regulates the dynamic balance between human activated regulatory and effector T cells: implications for antiviral and autoimmune responses
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DOI：
10.1111/j.1365-2567.2010.03280.x
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发表时间：
2010-09-01
期刊：
影响因子：
6.4
通讯作者：
Andrade, Felipe
中科院分区：
文献类型：
--
作者：
Golding, Amit;Rosen, Antony;Andrade, Felipe
对病原体充分的效应反应及其在病原体清除后的失活对维持免疫稳态至关重要。这个过程包括T细胞效应（Teff）激活的初始阶段，随后是调节性T细胞（Tregs）的扩增，这是一种限制Teff功能的独特细胞群。然而，关于调节这些细胞群之间平衡的机制，仍然存在一些重要的问题。利用体外系统模拟人外周血单核细胞（PBMC）中t细胞的激活，我们分析了Treg和Teff的激活模式，特别关注I型干扰素（IFN-I）的作用。有趣的是，我们发现，无论是外源性添加还是内源性诱导的ifn - α，都抑制了CD4+ FoxP3HI ifn - γ -负激活treg （aTregs）的产生，同时促进了CD4+ FoxP3Low/负ifn - γ - Pos激活Teffs （aTeffs）的增殖。我们还发现，ifn - α介导的白细胞介素(IL)-2产生的抑制可能在ifn - α诱导的aTregs抑制中发挥重要作用。为了在慢性ifn - α升高的疾病状态下验证我们的发现，我们研究了系统性红斑狼疮（SLE）。发现SLE患者的血浆中含有抑制atregg生成的IFN-I活性。此外，抗cd3激活的SLE pbmc表现出aTeffs的优先扩增，而aTreg数量的增加非常有限。总之，这些观察结果支持一个模型，即ifn - α的短暂产生（如在早期抗病毒反应中所见）可能通过延迟aTreg的产生来促进CD4效应功能，但ifn - α的慢性升高可能使aTeff:aTreg平衡向aTeffs和自身免疫倾斜。
P>An adequate effector response against pathogens and its subsequent inactivation after pathogen clearance are critical for the maintenance of immune homeostasis. This process involves an initial phase of T-cell effector (Teff) activation followed by the expansion of regulatory T cells (Tregs), a unique cell population that limits Teff functions. However, significant questions remain unanswered about the mechanisms that regulate the balance between these cell populations. Using an in vitro system to mimic T-cell activation in human peripheral blood mononuclear cells (PBMC), we analysed the patterns of Treg and Teff activation, with special attention to the role of type I interferon (IFN-I). Interestingly, we found that IFN-alpha, either exogenously added or endogenously induced, suppressed the generation of CD4+ FoxP3HI IFN-gamma Neg activated Tregs (aTregs) while simultaneously promoting propagation of CD4+ FoxP3Low/Neg IFN-gamma Pos activated Teffs (aTeffs). We also showed that IFN-alpha-mediated inhibition of interleukin (IL)-2 production may play an essential role in IFN-alpha-induced suppression of aTregs. In order to test our findings in a disease state with chronically elevated IFN-alpha, we investigated systemic lupus erythematosus (SLE). Plasma from patients with SLE was found to contain IFN-I activity that suppressed aTreg generation. Furthermore, anti-CD3 activated SLE PBMCs exhibited preferential expansion of aTeffs with a very limited increase in aTreg numbers. Together, these observations support a model whereby a transient production of IFN-alpha (such as is seen in an early antiviral response) may promote CD4 effector functions by delaying aTreg generation, but a chronic elevation of IFN-alpha may tip the aTeff:aTreg balance towards aTeffs and autoimmunity.