Roles of CD8⁺ tissue-resident memory T cells in the liver fibrosis resolution

Background: Non-alcoholic steatohepatitis (NASH) is a chronic liver disease that can progress to liver fibrosis. Recent clinical advances suggest a reversibility of liver fibrosis, but the cellular and molecular mechanisms remain unclarified. Methods: To explore key features associated with the resolution process in liver fibrosis, we applied a unique murine model, in which mice were fed high-fat and high-cholesterol (HFHC) diet for 24 weeks, and then switched to a normal diet (RES mice). The dynamic change of intrahepatic immune cells during NASH development and the resolution was examined. Results: We found that the number of intrahepatic CD8T cells remained significantly high in RES mice compared to normal diet-fed mice at 8 weeks following the diet switch. Single-cell transcriptome analysis revealed that the majority of intrahepatic CD8T cells showed Cd44⁺Sell^-S1pr1^- tissue-resident memory T (Trm) phenotypes in NASH resolution. The depletion of CD8T cells during the resolution phase prevented recovery from liver inflammation and fibrosis. On the other hand, adaptive transfer of CD8+Trm cells derived from RES mice achieved a significant suppression of the liver inflammation and fibrosis in methionine choline deficient diet-induced liver fibrosis model. Conclusion: These results collectively provide a novel fibrolytic role of CD8+Trm cells in NASH resolution, suggesting a potential clinical therapeutic target for patients with NASH.