Itch expression by Treg cells controls Th2 inflammatory responses
Itch expression by Treg cells controls Th2 inflammatory responses
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Treg 细胞的痒表达控制 Th2 炎症反应
DOI：
10.1172/jci69355
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发表时间：
2013-11-01
影响因子：
15.9
通讯作者：
Liu, Yun-Cai
中科院分区：
文献类型：
--
作者：
Jin, Hyung-Seung;Park, Yoon;Liu, Yun-Cai
调节性T （Treg）细胞通过限制自身免疫和炎症反应来维持免疫稳态。Treg的分化、维持和功能由转录因子Foxp3控制。然而，Treg细胞调控的确切分子机制仍然难以捉摸。在这里，我们发现Treg细胞特异性消融小鼠E3泛素连接酶Itch导致大量多器官淋巴细胞浸润和皮肤病变，慢性T细胞活化，以及严重抗原诱导的气道炎症的发展。令人惊讶的是，Treg细胞的Foxp3表达、稳态和体外和体内抑制能力不受瘙痒缺乏的影响。我们发现，在没有瘙痒的情况下，Treg细胞的Th2细胞因子表达增加。命运图谱显示，一部分Treg细胞失去了Foxp3的表达，这与瘙痒无关。然而，Th2细胞因子在Itch(-/-) foxp3阴性的“前treg”细胞中过度增强，而不改变转化的百分比。Treg细胞中靶向敲低Th2转录调节因子可阻止Th2细胞因子的产生。本研究揭示了Itch(-/-) Treg细胞获得th2样特性的机制，该机制不依赖于Foxp3功能和Treg细胞稳定性。
Regulatory T (Treg) cells maintain immune homeostasis by limiting autoimmune and inflammatory responses. Treg differentiation, maintenance, and function are controlled by the transcription factor Foxp3. However, the exact molecular mechanisms underlying Treg cell regulation remain elusive. Here, we show that Treg cell-specific ablation of the E3 ubiquitin ligase Itch in mice caused massive multiorgan lymphocyte infiltration and skin lesions, chronic T cell activation, and the development of severe antigen-induced airway inflammation. Surprisingly, Foxp3 expression, homeostasis, and the in vitro and in vivo suppressive capability of Treg cells were not affected by Itch deficiency. We found that the expression of Th2 cytokines by Treg cells was increased in the absence of Itch. Fate mapping revealed that a fraction of Treg cells lost Foxp3 expression independently of Itch. However, Th2 cytokines were excessively augmented in Itch(-/-) Foxp3-negative "ex-Treg" cells without altering the percentage of conversion. Targeted knockdown of Th2 transcriptional regulators in Treg cells prevented Th2 cytokine production. The present study unveils a mechanism of Itch(-/-) Treg cell acquisition of Th2-like properties that is independent of Foxp3 function and Treg cell stability.