Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
Hepatology. 2014 May;59(5):1715-25. doi: 10.1002/hep.26968. Epub 2014 Mar 27.
Uncontrolled natural killer (NK) cell activation during the early response to acute viral infection can lead to severe immunopathology, and the mechanisms NK cells use to achieve self-tolerance in such contexts are currently unclear. Here, NK cells up-regulated a coinhibitory receptor, T-cell Ig and ITIM domain (TIGIT), during challenge with the viral double-stranded RNA (dsRNA) analog poly I:C. Blocking TIGIT by antibody treatment in vivo or a genetic deficiency in Tigit enhanced NK cell activation and aggravated liver injury in a poly I:C/D-GalN-induced model of acute fulminant hepatitis, suggesting that TIGIT is normally required for protecting against NK cell-mediated liver injury. Furthermore, adoptively transferring Tigit(-/-) NK cells into NK cell-deficient Nfil3(-/-) mice also resulted in elevated liver injury. Reconstituting Kupffer cell-depleted mice with poliovirus receptor (PVR/CD155, a TIGIT ligand)-silenced Kupffer cells led to aggravated liver injury in a TIGIT-dependent manner. Blocking TIGIT in an NK-Kupffer cell coculture in vitro enhanced NK cell activation and interferon-gamma (IFN-γ) production in a PVR-dependent manner. We also found that TIGIT was up-regulated selectively on NK cells and protected against liver injury in an acute adenovirus infection model in both an NK cell- and Kupffer cell-dependent manner. Knocking down PVR in Kupffer cells resulted in aggravated liver injury in response to adenovirus infection in a TIGIT-dependent manner.
TIGIT negatively regulates NK-Kupffer cell crosstalk and alleviates liver injury in response to poly I:C/D-GalN challenge or acute adenovirus infection, suggesting a novel mechanism of NK cell self-tolerance in liver homeostasis during acute viral infection.
在急性病毒感染的早期反应中，未控制的自然杀伤 (NK) 细胞激活可导致严重的免疫病理学，而 NK 细胞在这种情况下实现自身耐受的机制目前尚不清楚。在这里，NK 细胞在受到病毒双链 RNA (dsRNA) 类似物聚 I:C 的挑战时上调了一种共抑制受体，T 细胞免疫球蛋白和 ITIM 结构域 (TIGIT)。体内用抗体治疗阻断 TIGIT 或 Tigit 基因缺失增强了聚 I:C/D-GalN 诱导的急性暴发性肝炎模型中的 NK 细胞激活和肝损伤，表明 TIGIT 通常是防止 NK 细胞介导的肝损伤所必需的。此外，将 Tigit(-/-)NK 细胞过继转移到 NK 细胞缺陷的 Nfil3(-/-)小鼠中也导致肝损伤升高。用沉默了脊髓灰质炎病毒受体 (PVR/CD155，TIGIT 配体) 的枯否细胞重建耗尽枯否细胞的小鼠，导致以 TIGIT 依赖的方式加重肝损伤。体外 NK-枯否细胞共培养中阻断 TIGIT 以 PVR 依赖的方式增强了 NK 细胞激活和干扰素-γ (IFN-γ) 的产生。我们还发现，TIGIT 选择性地上调于 NK 细胞上，并以 NK 细胞和枯否细胞依赖的方式防止急性腺病毒感染模型中的肝损伤。在枯否细胞中敲低 PVR 导致以 TIGIT 依赖的方式加重对腺病毒感染的肝损伤。
TIGIT 负调节 NK-枯否细胞相互作用，并减轻对聚 I:C/D-GalN 挑战或急性腺病毒感染的肝损伤，提示在急性病毒感染期间，NK 细胞在肝脏稳态中的自身耐受存在一种新机制。
