TIGIT impairs NK cell antifibrotic activity through the IFNγ– IFI30 axis in schistosomiasis-induced liver fibrosis

Hui Peng¹Jing Zhang¹Xiaocheng Zhang¹hao zhou¹Lijun Cui¹Fangfang Xu¹Tingting Jiang¹Jianhai Yin¹Yuan Hu¹Yujuan Shen¹Shaohong Lu^2*Jianping Cao^1*

• ¹National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), Shanghai, China
• ²Hangzhou Medical College, Hangzhou, China

Background: Schistosomiasis-induced liver fibrosis is a major cause of morbidity and mortality, driven largely by dysregulated immune responses. Natural killer (NK) cells are critical antifibrotic effectors; however, their functions are often impaired during chronic infection. Methods: To investigate the mechanism underlying NK cell dysfunction, we established a murine model of Schistosoma japonicum infection and assessed NK cell phenotype, cytokine production, and fibrosis markers. A TIGIT-knockdown NK92 cell line and NK cell–specific Tigit-deficient mice were generated to examine the regulatory role of TIGIT. RNA sequencing and functional assays were used to identify downstream effectors. Results: TIGIT expression on hepatic NK cells increased progressively during infection and was accompanied by reduced secretion of interferon-γ and granzyme B, indicating functional exhaustion. TIGIT knockdown restored NK cell cytotoxicity against hepatic stellate cells and upregulated interferon-induced transmembrane protein IFI30, enhancing NK cell proliferation through an interferon-γ–dependent mechanism. In vivo, NK cell–specific TIGIT deletion alleviated hepatic inflammation, collagen deposition, and fibrosis marker expression in schistosomiasis-infected mice. Conclusion: These findings identify TIGIT as a key negative regulator of NK cell antifibrotic activity and reveal an immunoregulatory TIGIT–interferon-γ–IFI30 axis that drives NK cell dysfunction and promotes schistosomiasis-induced liver fibrosis. Targeting this pathway may provide a new immunotherapeutic strategy for fibrotic diseases associated with chronic infection.