TIGIT Safeguards Liver Regeneration Through Regulating Natural Killer Cell-Hepatocyte Crosstalk
TIGIT Safeguards Liver Regeneration Through Regulating Natural Killer Cell-Hepatocyte Crosstalk
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TIGIT 通过调节自然杀伤细胞-肝细胞串扰来保护肝脏再生
DOI：
10.1002/hep.27245
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发表时间：
2014-10-01
期刊：
影响因子：
13.5
通讯作者：
Tian, Zhigang
中科院分区：
文献类型：
--
作者：
Bi, Jiacheng;Zheng, Xiaodong;Tian, Zhigang
先天免疫，特别是自然杀伤（NK）细胞的过度激活，对肝再生有害;然而，在肝再生过程中限制NK细胞过度激活的分子机制仍然是难以捉摸的。在这里，我们表明，共抑制受体，T细胞IG和ITIM结构域（TIGIT），选择性上调NK细胞，沿着高表达的配体，脊髓灰质炎病毒受体（PVR/CD 155），在肝细胞再生过程中。TIGIT的缺乏会损害体内肝脏再生，同时沿着NK细胞的过度激活和NK衍生的干扰素-γ（IFN-）产生增加。我们还表明，NK细胞的耗竭和IFN-γ的缺乏，而不是RAG 1的缺乏，挽救了由TIGIT的缺乏引起的肝再生受损。将Tigit（-/-）NK细胞连续转移到NK缺陷型Nfil 3（-/-）小鼠中足以导致肝再生受损。另一方面，在肝细胞中沉默PVR在体内挽救了由TIGIT缺陷引起的受损的肝再生，而在NK-肝细胞共培养物中阻断TIGIT在体外增加了NK细胞的IFN-γ产生。结论：TIGIT通过负性调节NK细胞与肝细胞的相互作用促进肝再生。这一发现表明了NK细胞对宿主再生性增生的自身耐受性的新机制。（肝病学2014;60：1389-1398）
Overactivation of innate immunity, particularly natural killer (NK) cells, is harmful to liver regeneration; however, the molecular mechanisms that limit NK cell overactivation during liver regeneration are still elusive. Here we show that a coinhibitory receptor, T cell Ig and ITIM domain (TIGIT), was selectively up-regulated on NK cells, along with high expression of its ligand, poliovirus receptor (PVR/CD155), on hepatocytes during liver regeneration. The absence of TIGIT impaired liver regeneration in vivo, along with overactivation of NK cells and higher NK-derived interferon-gamma (IFN-) production. We also show that both depletion of NK cells and deficiency of IFN-, but not deficiency of RAG1, rescued impaired liver regeneration caused by the absence of TIGIT. Adoptive transfer of Tigit(-/-) NK cells into NK-deficient Nfil3(-/-) mice sufficiently led to impairment of liver regeneration. On the other hand, silencing PVR in hepatocytes rescued impaired liver regeneration caused by TIGIT deficiency in vivo, while blockade of TIGIT in NK-hepatocyte coculture increased IFN- production by NK cells in vitro. Conclusion: TIGIT is a safeguard molecule to improve liver regeneration through negatively regulating NK-hepatocyte crosstalk. This finding suggests a novel mechanism of NK cell self-tolerance towards regenerative hyperplasia of the host. (Hepatology 2014;60:1389-1398)