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

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.

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.

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.

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.