| First Author | Liu Q | Year | 2022 |
| Journal | Cell Death Dis | Volume | 13 |
| Issue | 4 | Pages | 289 |
| PubMed ID | 35361750 | Mgi Jnum | J:323937 |
| Mgi Id | MGI:7263508 | Doi | 10.1038/s41419-022-04739-3 |
| Citation | Liu Q, et al. (2022) IL-1beta-activated mTORC2 promotes accumulation of IFN-gamma(+) gammadelta T cells by upregulating CXCR3 to restrict hepatic fibrosis. Cell Death Dis 13(4):289 |
| abstractText | 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 gammadelta T cells are involved in liver fibrosis, the precise role and mechanisms of gammadelta T cells migrating to fibrotic liver have not been elucidated. Here, we aim to investigate the functional subsets of gammadelta T cells in hepatic fibrosis and to further explore the underlying causes and drivers of migration. In this study, we observed that gammadelta T cells accumulate in fibrotic liver. Adoptive transfer of gammadelta T, especially Vgamma4 gammadelta T subset, can significantly alleviate liver fibrosis. In addition, CCl4 treatment also leads to activation of mTOR signaling in gammadelta T cells. Genetic deletion of the Rictor gene, but not Raptor, in gammadelta T cells markedly exacerbated liver fibrosis. Mechanistically, CCl4-induced liver injury causes macrophage accumulation in the liver, and IL-1beta produced by macrophages promotes mTORC2 signaling activation in gammadelta T cells, which upregulates T-bet expression and eventually promotes CXCR3 transcription to drive gammadelta T cell migration. Moreover, hepatic gammadelta 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-1beta-activated mTORC2 signaling in gammadelta T cells upregulates CXCR3 expression, which is critical for IFN-gamma(+) gammadelta T cells migration into the liver and amelioration of liver fibrosis. Our findings indicate that targeting the mTORC2 or CXCR3 in gammadelta T cells could be considered as a promising approach for gammadelta T cell immunotherapy against liver fibrosis. |
