CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Cell Death Differ. 2013 Mar;20(3):456-64. doi: 10.1038/cdd.2012.141. Epub 2012 Nov 16.
Activating and inhibitory receptors control natural killer (NK) cell activity. T-cell immunoglobulin and ITIM (immunoreceptor tyrosine-based inhibition motif) domain (TIGIT) was recently identified as a new inhibitory receptor on T and NK cells that suppressed their effector functions. TIGIT harbors the immunoreceptor tail tyrosine (ITT)-like and ITIM motifs in its cytoplasmic tail. However, how its ITT-like motif functions in TIGIT-mediated negative signaling is still unclear. Here, we show that TIGIT/PVR (poliovirus receptor) engagement disrupts granule polarization leading to loss of killing activity of NK cells. The ITT-like motif of TIGIT has a major role in its negative signaling. After TIGIT/PVR ligation, the ITT-like motif is phosphorylated at Tyr225 and binds to cytosolic adapter Grb2, which can recruit SHIP1 to prematurely terminate phosphatidylinositol 3-kinase (PI3K) and MAPK signaling, leading to downregulation of NK cell function. In support of this, Tyr225 or Asn227 mutation leads to restoration of TIGIT/PVR-mediated cytotoxicity, and SHIP1 silencing can dramatically abolish TIGIT/PVR-mediated killing inhibition.
激活和抑制受体控制自然杀伤 (NK) 细胞的活性。T 细胞免疫球蛋白和 ITIM（免疫受体酪氨酸抑制基序）结构域（TIGIT）最近被鉴定为 T 和 NK 细胞上的一种新的抑制性受体，抑制其效应功能。TIGIT 在其细胞质尾部包含免疫受体尾部酪氨酸 (ITT)-样和 ITIM 基序。然而，其 ITT-样基序在 TIGIT 介导的负信号传导中的作用仍不清楚。在这里，我们表明 TIGIT/PVR（脊髓灰质炎病毒受体）的结合会破坏颗粒的极化，导致 NK 细胞丧失杀伤活性。TIGIT 的 ITT-样基序在其负信号传导中起着主要作用。在 TIGIT/PVR 连接后，ITT-样基序在 Tyr225 处磷酸化，并与细胞质衔接蛋白 Grb2 结合，后者可以募集 SHIP1 过早终止磷脂酰肌醇 3-激酶 (PI3K) 和 MAPK 信号传导，导致 NK 细胞功能下调。为此，Tyr225 或 Asn227 突变导致 TIGIT/PVR 介导的细胞毒性恢复，并且 SHIP1 沉默可以显著消除 TIGIT/PVR 介导的杀伤抑制。
