Seattle Children's Research Institute, Center for Immunity and Immunotherapies, Seattle, Washington, USA.
Benaroya Research Institute, Immunology Program, Seattle, Washington, USA.
JCI Insight. 2017 Oct 5;2(19):94275. doi: 10.1172/jci.insight.94275.
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.
Foxp3+ Tregs 具有强大的免疫抑制活性，对于维持免疫稳态和自身耐受至关重要。Treg 发育或功能缺陷会导致意外的免疫激活和自身免疫。尽管 Treg 生物学最近取得了进展，但我们仍不完全了解控制这些细胞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分裂蛋白 8（DOCK8）的一个关键作用，细胞分裂蛋白 8 是细胞骨架重排、细胞迁移和免疫细胞存活所必需的鸟嘌呤核苷酸交换因子，在控制 Treg 适应性及其功能方面发挥着重要作用。由于 T 细胞的过度激活和促炎细胞因子的产生，Treg 特异性 DOCK8 缺失导致小鼠自发的多器官炎症。此外，我们还表明，DOCK8 缺陷型 Treg 在竞争适应性和体内抑制功能方面存在缺陷。此外，DOCK8 通过 STAT5 依赖性方式控制 IL-2 信号，这对 Treg 的维持和竞争适应性至关重要。我们的研究为 DOCK8 在 Treg 和免疫调节中的重要功能提供了潜在的新见解，并解释了与 DOCK8 缺乏相关的自身免疫表现。
