TIGIT safeguards liver regeneration through regulating... : Hepatology (original) (raw)

Liver Injury/Regeneration

TIGIT safeguards liver regeneration through regulating natural killer cell-hepatocyte crosstalk

Bi, Jiacheng1; Zheng, Xiaodong1; Chen, Yongyan1; Wei, Haiming1,2; Sun, Rui1,2; Tian, Zhigang1,2

From the 1 Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China; 2Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China.

Received 15 January 2014; accepted 26 May 2014

Published online 25 August 2014.

Address reprint requests to: Zhigang Tian, Ph.D., or Rui Sun, M.D., Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China. E-mail:[email protected] or [email protected]; fax: +86–551–6360–0832.

Potential conflict of interest: Nothing to report.

Supported by the Ministry of Science & Technology of China (973 Basic Science Project 2013CB530506, 2013CB944902) and the Natural Science Foundation of China (#31270954, #91029303).

Abstract

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-γ) production. We also show that both depletion of NK cells and deficiency of IFN-γ, 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-γ 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)