The accumulation of effector CD8+ T cells in the livers of obese patients with non-alcoholic fatty liver disease (NAFLD) is considered an early contributing factor to liver damage and the progression to non-alcoholic steatohepatitis (NASH), fibrosis and hepatocellular carcinoma (HCC). The precise mechanisms governing the activation of hepatic T cells in NAFLD remain unknown.
Here we report that the increased generation of reactive oxygen species (ROS) in hepatocytes in NAFLD results in the oxidation and inactivation of protein tyrosine phosphatases (PTPs) in infiltrating CD8+ T cells. Oxidised PTPs in T cells included PTPN2, PTP1B, SHP-1 and SHP-2 that tune T cell signaling to temper T cell responses. The oxidative inactivation of PTPs enhanced antigen-induced T cell activation and promoted inflammation, liver damage and NASH/fibrosis in high fat fed mice. This was accompanied by a heightened T cell antioxidant defence response that was also evident in hepatic CD8+ T cells from patients with NAFLD. The deletion of PTPN2 in T cells in high fat fed mice resulted in the accumulation of antigen-experienced effector CD8+ T cells, hepatic inflammation, liver damage, fibrosis and preneoplastic nodules, whereas T cell PTPN2 deletion promoted inflammation and fibrosis and exacerbated the chemical carcinogen-induced development of HCC in mice.
Our results demonstrate that the oxidation and inactivation of T cell tyrosine-phosphatases in NAFLD can result in a loss of T cell tolerance, inflammation and liver damage to drive NASH/fibrosis and HCC. Our findings establish a new paradigm for redox crosstalk in hepatic pathophysiology.