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

Abstract

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 ofinfection and assessed NK cell phenotype, cytokine production, and fibrosis markers. A-knockdown NK92 cell line and NK cell-specific-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.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., NK cell-specificdeletion 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.