Natural killer (NK) cell activation is well orchestrated by a wide array of NK cell receptor repertoire. T-cell immunoglobulin and ITIM domain (TIGIT) receptor was recently defined as an inhibitory receptor that is expressed on NK cells and T cells. TIGIT receptor/poliovirus receptor (PVR) ligand engagement signaling inhibits cytotoxicity mediated by NK and CD8(+) T cells. However, it is unclear how TIGIT/PVR signaling regulates cytokine secretion in NK cells. Here we show that TIGIT/PVR engagement suppresses interferon-gamma (IFN-gamma) production of NK cells. TIGIT transgenic NK cells generate less IFN-gamma undergoing TIGIT/PVR ligation. Moreover, TIGIT knock-out NK cells produce much more IFN-gamma. TIGIT/PVR ligation signaling mediates suppression of IFN-gamma production via the NF-kappaB pathway. We identified a novel adaptor beta-arrestin 2 that associates with phosphorylated TIGIT for further recruitment of SHIP1 (SH2-containing inositol phosphatase 1) through the ITT-like motif. Importantly, SHIP1, but not other phosphatases, impairs the TNF receptor-associated factor 6 (TRAF6) autoubiquitination to abolish NF-kappaB activation, leading to suppression of IFN-gamma production in NK cells.

中文翻译：

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T 细胞免疫球蛋白和 ITIM 结构域 (TIGIT) 受体/脊髓灰质炎病毒受体 (PVR) 配体结合通过 β-抑制蛋白 2 介导的负信号抑制自然杀伤细胞的干扰素-γ 产生。

自然杀伤 (NK) 细胞的激活是由各种 NK 细胞受体库精心策划的。T 细胞免疫球蛋白和 ITIM 结构域 (TIGIT) 受体最近被定义为在 NK 细胞和 T 细胞上表达的抑制性受体。TIGIT 受体/脊髓灰质炎病毒受体 (PVR) 配体参与信号抑制由 NK 和 CD8(+) T 细胞介导的细胞毒性。然而，目前尚不清楚 TIGIT/PVR 信号如何调节 NK 细胞中的细胞因子分泌。在这里，我们展示了 TIGIT/PVR 参与抑制了 NK 细胞的干扰素-γ（IFN-γ）的产生。TIGIT 转基因 NK 细胞在进行 TIGIT/PVR 连接时产生较少的 IFN-γ。此外，TIGIT 敲除 NK 细胞会产生更多的 IFN-γ。TIGIT/PVR 结扎信号通过 NF-kappaB 通路介导干扰素-γ 生产的抑制。我们确定了一种新的适配器 beta-arrestin 2，它与磷酸化的 TIGIT 相关联，用于通过 ITT 样基序进一步招募 SHIP1（含 SH2 的肌醇磷酸酶 1）。重要的是，SHIP1，而不是其他磷酸酶，会损害 TNF 受体相关因子 6 (TRAF6) 自动泛素化以消除 NF-kappaB 激活，从而抑制 NK 细胞中 IFN-γ 的产生。