Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus
Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus
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DOI：
10.1073/pnas.0903158107
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发表时间：
2010-01-05
影响因子：
11.1
通讯作者：
Riemekasten, Gabriela
中科院分区：
文献类型：
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作者：
Humrich, Jens Y.;Morbach, Henner;Riemekasten, Gabriela
系统性红斑狼疮（SLE）中调节性T细胞（Treg）紊乱的起源和后果尚不清楚。在（NZBxNZW） F-1狼疮小鼠模型中，我们发现CD4(+)Foxp3(+) Treg在外周淋巴器官中未能维持竞争性池大小，导致CD4(+)Foxp3(+) Treg和CD4(+)Foxp3（-）常规T细胞（Tcon）的进行性稳态失衡。此外，Treg获得的表型变化让人想起IL-2缺乏，伴随着IL-2产生的Tcon的逐渐下降和激活的ifn - γ产生的效应物Tcon的增加。尽管如此，狼疮易感小鼠的Treg在功能上是完整的，能够影响疾病的进程。疾病早期全身性IL-2水平降低可促进Tcon过度活跃，诱导Treg和效应Tcon失衡，并强烈加速疾病进展。相比之下，IL-2通过促进内源性Treg的稳态增殖，部分恢复了Treg和效应物Tcon的平衡，并阻碍了既定疾病的进展。因此，Treg-IL-2轴的获得性和自我扩增性破坏本质上促成了Tcon过度活跃和小鼠狼疮的发展。这种体内平衡Treg紊乱的可逆性为SLE的治疗提供了有希望的方法。
The origins and consequences of a regulatory T cell (Treg) disorder in systemic lupus erythematosus (SLE) are poorly understood. In the (NZBxNZW) F-1 mouse model of lupus, we found that CD4(+)Foxp3(+) Treg failed to maintain a competitive pool size in the peripheral lymphoid organs resulting in a progressive homeostatic imbalance of CD4(+)Foxp3(+) Treg and CD4(+)Foxp3(-) conventional T cells (Tcon). In addition, Treg acquired phenotypic changes that are reminiscent of IL-2 deficiency concomitantly to a progressive decline in IL-2-producing Tcon and an increase in activated, IFN-gamma-producing effector Tcon. Nonetheless, Treg from lupusprone mice were functionally intact and capable to influence the course of disease. Systemic reduction of IL-2 levels early in disease promoted Tcon hyperactivity, induced the imbalance of Treg and effector Tcon, and strongly accelerated disease progression. In contrast, administration of IL-2 partially restored the balance of Treg and effector Tcon by promoting the homeostatic proliferation of endogenous Treg and impeded the progression of established disease. Thus, an acquired and self-amplifying disruption of the Treg-IL-2 axis contributed essentially to Tcon hyperactivity and the development of murine lupus. The reversibility of this homeostatic Treg disorder provides promising approaches for the treatment of SLE.