Co-inhibitory receptor TIGIT inhibits CD8+T mediated hepatocellular carcinoma

Abstract

Abstract Chronic hepatitis B virus (HBV) pathogenesis is widely accepted as numerous immune response inducing prolonged inflammation, cirrhosis and lastly hepatocellular carcinoma(HCC). However, the potential theory of HBV tolerance and the immune-mediated HCC development has not been clearly defined currently. We found here that hepatic CD8+T cells of HBsAg-transgenic mice (HBs-tg) express remarkably high levels of co-inhibitory receptor T cell Ig and ITIM domain (TIGIT) with age. Co-inhibitory pathway blockade in HBs-tg mice initiated regional chronic inflammation sequentially inside the liver which reflected by gradually rising ALT level and hepatic fibrosis. TIGIT blockade gave rise to the emerging of HBsAg-specific CTLs and rescued CD8+T cells function by increased proliferation and interferon-γ(IFN-γ) and CD107a production in liver. Besides, HBsAg vaccination to TIGIT-blockade mice triggered the development of HCC. Breeding HBs-tg TIGIT−/−mice showed spontaneous chronic inflammation in life and got HCC toward HBsAg vaccination. CD8+T depletion during TIGIT blockade alleviates liver inflammation in HBs-tg mice. While depleting CD8+T cells start from the vaccination stage till harvest in TIGIT-blockade mice abolishes HCC formation. Conclusion High co-inhibitory receptor expression on CD8+T cell may be a contributing factor for HBV tolerance. Our studies reveal a new molecular pathway which causes chronic hepatic diseases.