Innate lymphoid cells (ILCs) are a family of developmentally related leukocytes that rapidly secrete polarized sets of cytokines to combat infection and promote tissue repair at mucosal barriers. Among them, group 3 ILCs (ILC3s) play an important role in maintenance of the gut homeostasis by producing IL-22, and their development and function critically depend on the transcription factor RORγt. Although recent evidence indicates that RORγt⁺ ILC3s are reduced in the gut in the absence of the Cdc42 activator DOCK8 (dedicator of cytokinesis 8), the underlying mechanism remains unclear. We found that genetic deletion of Dock8 in RORγt⁺-lineage cells markedly reduced ILC3s in the lamina propria of the small intestine. By analyzing BrdU incorporation, it was revealed that DOCK8 deficiency did not affect the cell proliferation. Furthermore, when lineage marker-negative (Lin^–) α4β7⁺ CD127⁺ RORγt^– fetal liver cells were cultured with OP9 stromal cells in the presence of stem cell factor (SCF) and IL-7 in vitro, RORγt⁺ ILC3s normally developed irrespective of DOCK8 expression. However, DOCK8-deficient ILC3s exhibited a severe defect in survival of ILC3s under the condition with or without IL-7. Similar defects were observed when we analyzed Dock8^VAGR mice having mutations in the catalytic center of DOCK8, thereby failing to activate Cdc42. Thus, DOCK8 acts in cell-autonomous manner to control survival of ILC3s in the gut through Cdc42 activation.

中文翻译：

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DOCK8 通过 Cdc42 激活控制肠道中第 3 组先天淋巴细胞的存活

先天淋巴细胞 (ILC) 是一个发育相关的白细胞家族，可快速分泌极化的细胞因子组来对抗感染并促进黏膜屏障处的组织修复。其中，第 3 组 ILCs (ILC3s) 通过产生 IL-22 在维持肠道稳态中发挥重要作用，其发育和功能严重依赖于转录因子 RORγt。尽管最近的证据表明，在没有 Cdc42 激活剂 DOCK8（胞质分裂的贡献者 8）的情况下，RORγt ^{+ ILC3s 在肠道中减少，但潜在的机制仍不清楚。}我们发现RORγt ^+中Dock8的基因缺失- 谱系细胞显着减少小肠固有层中的 ILC3。通过分析BrdU掺入，发现DOCK8缺乏不影响细胞增殖。此外，当在体外存在干细胞因子 (SCF) 和 IL-7 的情况下，将谱系标记阴性 (Lin ^– ) α4β7 ⁺ CD127 ⁺ RORγt ^–胎儿肝细胞与 OP9 基质细胞一起培养时，RORγt ⁺ ILC3s 正常发育，与DOCK8 表达式。然而，DOCK8 缺陷型 ILC3 在有或没有 IL-7 的条件下表现出严重的 ILC3 存活缺陷。当我们分析Dock8 ^VAGR时观察到类似的缺陷在 DOCK8 的催化中心发生突变的小鼠，从而无法激活 Cdc42。因此，DOCK8 以细胞自主方式通过 Cdc42 激活控制肠道中 ILC3 的存活。