DOCK8 enforces immunological tolerance by promoting IL-2 signaling and immune synapse formation in Tregs
DOCK8 enforces immunological tolerance by promoting IL-2 signaling and immune synapse formation in Tregs
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DOI：
10.1172/jci.insight.94298
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发表时间：
2017-10-05
期刊：
影响因子：
8
通讯作者：
Geha, Raif S.
中科院分区：
文献类型：
--
作者：
Janssen, Erin;Kumari, Sudha;Geha, Raif S.
缺乏鸟嘌呤核苷酸交换因子DOCK 8的患者，其T细胞数量减少，体外功能受损，产生自身抗体，但很少发生自身免疫。我们发现，类似地，Dock 8（-/-）小鼠的数量减少，TcR的体外功能受损，但不发生自身免疫。相比之下，尽管TCLB的百分比和体外功能正常，但TCLB中具有选择性DOCK 8缺陷的小鼠发生淋巴细胞增殖、自身抗体和胃肠道炎症，这表明T效应细胞功能缺陷可能保护DOCK 8缺陷患者免受自身免疫。我们证明DOCK 8与STAT 5相关，并且对TcB中IL-2驱动的STAT 5磷酸化很重要。DOCK 8定位于Treg免疫突触（IS）的层状肌动蛋白环内。Dock 8（-/-）TcR具有异常的TCR驱动的肌动蛋白动力学、降低的肌动蛋白水平、改变的基因表达谱、不稳定的IS以及减少的信号分子募集和受损的共刺激分子CD 86的转内吞作用。这些数据表明，DOCK 8通过促进IL-2信号传导、TCR驱动的肌动蛋白动力学和TCR 4中的IS来实施免疫耐受。
Patients deficient in the guanine nucleotide exchange factor DOCK8 have decreased numbers and impaired in vitro function of Tregs and make autoantibodies, but they seldom develop autoimmunity. We show that, similarly, Dock8(-/-) mice have decreased numbers and impaired in vitro function of Tregs but do not develop autoimmunity. In contrast, mice with selective DOCK8 deficiency in Tregs develop lymphoproliferation, autoantibodies, and gastrointestinal inflammation, despite a normal percentage and in vitro function of Tregs, suggesting that deficient T effector cell function might protect DOCK8-deficient patients from autoimmunity. We demonstrate that DOCK8 associates with STAT5 and is important for IL-2-driven STAT5 phosphorylation in Tregs. DOCK8 localizes within the lamellar actin ring of the Treg immune synapse (IS). Dock8(-/-) Tregs have abnormal TCR-driven actin dynamics, decreased adhesiveness, an altered gene expression profile, an unstable IS with decreased recruitment of signaling molecules, and impaired transendocytosis of the costimulatory molecule CD86. These data suggest that DOCK8 enforces immunological tolerance by promoting IL-2 signaling, TCR-driven actin dynamics, and the IS in Tregs.