The Inhibitory T Cell Receptors PD1 and 2B4 Are Differentially Regulated on CD4 and CD8 T Cells in a Mouse Model of Non-alcoholic Steatohepatitis

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.

Polymorphisms in Interleukin 13 Signaling and Interacting Genes Predict Advanced Fibrosis and Hepatocellular Carcinoma Development in Non-Alcoholic Steatohepatitis

“…It was recently shown that IL-13 producing cells, type 2 innate lymphoid cells (ILC2s), are destabilized in response to PD-1/PD-L1 pathway upon high-fat feeding resulting in impaired tissue metabolism [20]. Furthermore, PD-1 blockade showed a partial restore in type 2 innate axis and could serve as promising targets of immune-modulatory NASH therapy [21][22][23][24][25]. Importantly, PD-L1 was found to be responsible for HCC development in NASH via inducing the exhaustion of HCC-directed CD8 + T cells [26].…”

Role of CD4+ T-cells in the pathology of non-alcoholic fatty liver disease and related diseases

“…In mice fed an MCD, there was an increased frequency of Th17 cells in CD4 + T-cells in the liver tissue compared to that in the controls [279] . In this mouse model, the infiltration of Th17 cells in the liver triggered NASH pathogenesis and was important for the progression of liver fibrosis [119] . In MYC-ON mice fed with an MCD, the frequency of Th17 in liver tissue had increased compared to that in the controls [121] .…”

“…In C57BL/6 mice that were fed a methionine-and choline-deficient (MCD) diet for 8 weeks, the frequency of CD4 + T-cells increased significantly over the 8 weeks in hepatic mononuclear cells of the liver tissue compared to that in the controls. From the second week onward, intrahepatic CD4 + T-cells were activated (evaluated by CD25) with the progression in the pathological conditions [119] . Furthermore, in C57BL/6 mice that were fed an MCD diet for 8 weeks, the frequencies of CD4 + T-cells and CD8 + T-cells in CD45 + cells that respond to oxidative stress-derived antigens increased in the liver tissue over time, and CD3 + T-cells were activated (evaluated by CD69).…”

“…IL-17 causes steatosis in HepG2 cells in vitro in the presence of oleic and palmitic acids by interfering with the insulin signaling pathway [125] . In addition, IL-17 exacerbates palmitic acid-induced hepatocyte lipotoxicity in c-Jun N-terminal kinase (JNK)-dependent mice [119] . Thus, although IL-17 may suppress adipogenesis in adipocytes, it appears to promote fat accumulation in hepatocytes.…”

“…Blueberry combined with probiotics is a potential therapeutic target for NAFLD, which involves IL-22-mediated activation of Janus kinase 1/STAT3 signaling and the inhibition of the apoptotic factor B-cell lymphoma-2 (Bcl-2)-associated X protein (BAX) [299] . In vitro experiments have demonstrated that IL-22, in the absence of IL-17, prevents palmitate lipotoxicity via the phosphoinositide 3-kinase-mediated inhibition of JNK [119] .…”