IL-1β-activated mTORC2 promotes accumulation of IFN-γ+ γδ T cells by upregulating CXCR3 to restrict hepatic fibrosis

Liver fibrosis represents a severe stage of liver damage, with hallmarks of inflammation, hepatic stellate cell activation, and extracellular matrix accumulation. Although previous studies demonstrated gamma delta T cells are involved in liver fibrosis, the precise role and mechanisms of gamma delta T cells migrating to fibrotic liver have not been elucidated. Here, we aim to investigate the functional subsets of gamma delta T cells in hepatic fibrosis and to further explore the underlying causes and drivers of migration. In this study, we observed that gamma delta T cells accumulate in fibrotic liver. Adoptive transfer of gamma delta T, especially V gamma 4 gamma delta T subset, can significantly alleviate liver fibrosis. In addition, CCl4 treatment also leads to activation of mTOR signaling in gamma delta T cells. Genetic deletion of the Rictor gene, but not Raptor, in gamma delta T cells markedly exacerbated liver fibrosis. Mechanistically, CCl4-induced liver injury causes macrophage accumulation in the liver, and IL-1 beta produced by macrophages promotes mTORC2 signaling activation in gamma delta T cells, which upregulates T-bet expression and eventually promotes CXCR3 transcription to drive gamma delta T cell migration. Moreover, hepatic gamma delta T cells ameliorated liver fibrosis by cytotoxicity against activated hepatic stellate cells in FasL-dependent manner, and secrete IFN-gamma to inhibit the differentiation of pro-fibrotic Th17 cells. Thus, IL-1 beta-activated mTORC2 signaling in gamma delta T cells upregulates CXCR3 expression, which is critical for IFN-gamma(+) gamma delta T cells migration into the liver and amelioration of liver fibrosis. Our findings indicate that targeting the mTORC2 or CXCR3 in gamma delta T cells could be considered as a promising approach for gamma delta T cell immunotherapy against liver fibrosis.

Automated summary

This study reveals the accumulation of gamma delta T cells in fibrotic liver and their role in alleviating liver fibrosis. The activation of mTOR signaling in gamma delta T cells is observed during CCl4 treatment. IL-1 beta activation promotes the upregulation of CXCR3 expression through the mTORC2 signaling pathway in gamma delta T cells, leading to their migration into the liver and improvement of liver fibrosis.