Abstract
Infiltrating CD4 and CD8 T cells have been shown to worsen inflammatory liver damage in non-alcoholic steatohepatitis (NASH). Inhibitory T cell receptors such as the programmed cell death protein 1 (PD1) and the natural killer cell receptor 2B4 regulate the activity of CD4 and CD8 T cells and therefore play an important role in immune tolerance required in the liver. In this study, we investigated the expression profile of inhibitory T cell receptors on CD4 and CD8 T cells in a mouse model of NASH. Male B57BL/6J mice were fed a Western diet for 24 weeks. The expression levels of inhibitory receptors on the surface of intrahepatic and peripheral T cells were measured and correlated with markers of activation (CD107a, CD69, and CD44), metabolic disorder (serum triglycerides, serum cholesterol, γ-glutamyl transferase, hepatic triglycerides), inflammation (serum alanine aminotransferase and aspartate aminotransferase) and hepatic fibrosis (collagen 1A1, α-smooth muscle actin, hydroxyproline). Under Western diet, PD1 is exclusively upregulated on intrahepatic and peripheral CD8+ T cells, whereas the expression level on CD4 T cells is unaffected. In contrast, 2B4 is upregulated liver-specifically on both CD4 and CD8 T cells and unchanged on peripheral T cells. Upregulation of PD1 on CD8 T cells is restricted to CD8 effector memory T cells and correlates with lower levels of degranulation. Similarly, the inhibitory function of PD1 on intrahepatic CD4 T cells is shown by a lower CD69 and CD44 expression on PD1-positive CD4 T cells. In murine steatohepatitis, the upregulation of PD1 on CD8 T cells and 2B4 on CD4 and CD8 T cells potentially limits T cell-mediated liver damage. Therefore, these inhibitory T cell receptors could serve as promising targets of immune-modulatory NASH therapy.
Highlights
Non-alcoholic fatty liver disease is the most common hepatic disease in developed countries and is mostly accompanied by further manifestations of the metabolic syndrome like type 2 diabetes, hypertension, obesity and dyslipidemia
The last-named observation was shown by other investigators (Clapper et al, 2013) and seems to be an undesirable effect of this otherwise good performing non-alcoholic steatohepatitis (NASH) diet
In healthy mouse livers, cytotoxic CD8 T cells expressed higher levels of the inhibitory T cell receptors programmed cell death protein 1 (PD1) and 2B4 (Figure 3), whereas CD4 T helper cells expressed higher proportions of the activating receptors CD44 and CD69 (Figure 6), both compared to their blood counterparts
Summary
Non-alcoholic fatty liver disease is the most common hepatic disease in developed countries and is mostly accompanied by further manifestations of the metabolic syndrome like type 2 diabetes, hypertension, obesity and dyslipidemia. As a consequence of cirrhosis complications like variceal bleeding, hepatocellular carcinoma, spontaneous bacterial peritonitis or hepato-renal syndrome as well as the concomitantly augmented risk for cardiovascular events, NASH patients have a markedly reduced life expectancy (Ong and Younossi, 2007). According to another large United States study, examining data from 37500 adults, the prevalence of NAFLD duplicated within 20 years (Younossi et al, 2011; Younossi et al, 2018a,b). A better understanding of the mechanisms promoting the progression from simple steatosis to steatohepatitis is crucial
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