Abstract
Hepatitis B virus (HBV) can induce chronic inflammation, cirrhosis, and eventually hepatocellular carcinoma (HCC). Despite evidence suggesting a link between adaptive immunity and HBV-related diseases in humans, the immunopathogenic mechanisms involved are seldom described. Here we show that expression of TIGIT, a promising immune checkpoint in tumor immunotherapy, increases with age on hepatic CD8+ T cells in HBsAg-transgenic (HBs-tg) mice whose adaptive immune system is tolerant to HBsAg. TIGIT blockade or deficiency leads to chronic hepatitis and fibrosis, along with the emergence of functional HBsAg-specific cytotoxic T lymphocytes (CTLs), suggesting adaptive immune tolerance could be broken by TIGIT blockade or deficiency. Importantly, HBsAg vaccination further induces nonresolving inflammation and HCC in a CD8+ T cell-dependent manner in TIGIT-blocked or -deficient HBs-tg mice. Therefore, CD8+ T cells play an important role in adaptive immunity-mediated tumor progression and TIGIT is critical in maintenance of liver tolerance by keeping CTLs in homeostatic balance.
Highlights
Hepatitis B virus (HBV) can induce chronic inflammation, cirrhosis, and eventually hepatocellular carcinoma (HCC)
It has been demonstrated that HBs-tg mice, whose hepatocytes continuously express HBV surface antigens and adaptive immune system is tolerant to HBV, can be used as a model for HBV carriers[37,38]
Given that previous studies have shown that blockade of co-inhibitory receptors could restore CD8+ T cell functions in HBV-carrier people[23], we explored the consequences of blocking the TIGIT pathway in the HBs-tg mouse model
Summary
Hepatitis B virus (HBV) can induce chronic inflammation, cirrhosis, and eventually hepatocellular carcinoma (HCC). After weekly injections of the anti-TIGIT mAb, HBs-tg mice developed chronic hepatitis, as evidenced by gradually increased ALT levels that were significantly higher than those in rat IgGtreated HBs-tg mice (Fig. 1b). Fig. 1h), suggesting that TIGIT-blockade induces local chronic inflammation in the liver of HBs-tg mice.
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