DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling
DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling
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DOI：
10.1172/jci.insight.94275
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发表时间：
2017-10-05
期刊：
影响因子：
8
通讯作者：
Oukka, Mohamed
中科院分区：
文献类型：
--
作者：
Singh, Akhilesh K.;Eken, Ahmet;Oukka, Mohamed
Foxp 3（+）T细胞具有强免疫抑制活性，对维持免疫稳态和自身耐受至关重要。Treg发育或功能的缺陷导致无意的免疫激活和自身免疫。尽管最近在Treg生物学方面取得了进展，但我们仍然不完全了解这些细胞的发育和抑制功能的分子和细胞机制。在这里，我们已经证明了细胞质分裂的奉献者8（DOCK 8），细胞骨架重排，细胞迁移和免疫细胞存活所需的鸟嘌呤核苷酸交换因子在控制Treg适应性及其功能中的重要作用。Treg特异性DOCK 8缺失导致小鼠自发性多器官炎症，这是由于不受控制的T细胞活化和促炎细胞因子的产生。此外，我们发现DOCK 8缺陷型TcR在竞争适应性和体内抑制功能方面存在缺陷。此外，DOCK 8通过STAT 5依赖性方式控制IL-2信号传导，这对TcB的维持和竞争适应性至关重要。我们的研究为DOCK 8在THED和免疫调节中的基本功能提供了潜在的新见解，并解释了与DOCK 8缺陷相关的自身免疫表现。
Foxp3(+) Tregs possess potent immunosuppressive activity, which is critical for maintaining immune homeostasis and self-tolerance. Defects in Treg development or function result in inadvertent immune activation and autoimmunity. Despite recent advances in Treg biology, we still do not completely understand the molecular and cellular mechanisms governing the development and suppressive function of these cells. Here, we have demonstrated an essential role of the dedicator of cytokinesis 8 (DOCK8), guanine nucleotide exchange factors required for cytoskeleton rearrangement, cell migration, and immune cell survival in controlling Treg fitness and their function. Treg-specific DOCK8 deletion led to spontaneous multiorgan inflammation in mice due to uncontrolled T cell activation and production of proinflammatory cytokines. In addition, we show that DOCK8-deficient Tregs are defective in competitive fitness and in vivo suppressive function. Furthermore, DOCK8 controls IL-2 signaling, crucial for maintenance and competitive fitness of Tregs, via a STAT5-dependent manner. Our study provides potentially novel insights into the essential function of DOCK8 in Tregs and immune regulation, and it explains the autoimmune manifestations associated with DOCK8 deficiency.