Studying T Cell Responses to Hepatotropic Viruses in the Liver Microenvironment

Abstract

T cells play an important role in the clearance of hepatotropic viruses but may also cause liver injury and contribute to disease progression in chronic hepatitis B and C virus infections which affect millions of people worldwide. The liver provides a unique microenvironment of immunological tolerance and hepatic immune regulation can modulate the functional properties of T cell subsets and influence the outcome of a virus infection. Extensive research over the last years has advanced our understanding of hepatic conventional CD4+ and CD8+ T cells and unconventional T cell subsets and their functions in the liver environment during acute and chronic viral infections. The recent development of new small animal models and technological advances should further increase our knowledge of hepatic immunological mechanisms. Here we provide an overview of the existing models to study hepatic T cells and review the current knowledge about the distinct roles of heterogeneous T cell populations during acute and chronic viral hepatitis.

Τ cell-mediated adaptive immunity in the transition from metabolic dysfunction-associated steatohepatitis to hepatocellular carcinoma

“…T cells perform various physiological roles in the liver even before the emergence of MASH. These functions include the immune surveillance of the hepatic tissue, aimed at detecting and eliminating exogenous antigens or infected hepatocytes ( Lopez-Scarim et al, 2023 ), or even the retention of antigen-specific T cell tolerance, as it can occur upon the antigen cross-presentation mediated by liver sinusoidal endothelial cells (LSECs) ( Limmer et al, 2000 ). Additionally, the secretory phenotype of different T cell populations in the liver including both T helper and T cytotoxic cell subtypes, can have a significant impact in maintaining hepatic metabolic homeostasis, such as normal levels of insulin sensitivity ( Sim et al, 2023 ).…”

Glutaminolysis of CD4+ T Cells: A Potential Therapeutic Target in Viral Diseases

“…Curative treatment for HBV does not exist. 116 In contrast, chronic HCV, which affects approximately 58 million people worldwide, is associated with advanced liver disease and can induce hepatocellular carcinoma, which causes many extrahepatic manifestations. 79 , 117 , 118 …”

“…Curative treatment for HBV does not exist. 116 In contrast, chronic HCV, which affects approximately 58 million people worldwide, is associated with advanced liver disease and can induce hepatocellular carcinoma, which causes many extrahepatic manifestations. 79,117,118 In the hepatic microenvironment, hepatocytes interact with intrahepatic immune cells due to the open window structure of the hepatic sinusoids combined with the lack of basement membrane and low blood flow.…”

Idiosyncratic DILI: Immunology in Cases with Evidence Based on RUCAM

“…(2) monocytes (MCs) providing TNF-α, the interleukins IL-1β, IL-6, and IL-8, the chemokines CCL1, CCL2, CCL3, and CCL5, as well as growth factors such as granulocyte colony-stimulating factor (GCSF) and macrophage colony-stimulating factor(MCSF) [27];(3) hepatic stellate cells (HSCs)producing cytokines and growth factors capable of stimulating various hepatic cell types including TGFα, TGFβ, epidermal growth factor (EGF), hepatocyte growth factor (HGF), plateletderived growth factor (PDGF), stem cell factor, acidic and basic fibroblast growth factor (FGF), macrophage colony-stimulating factor, and platelet activating factor [28,29];(4) hepatic dendritic cells (HDCs)generating proinflammatory cytokines like IL-2, IL-6, IL-12,TNF-α, and INF-γ [30,31];(5) hepatic B cells (BCs)releasing the proinflammatory cytokines interferon (INF)-γ and TNFα [32];(6) hepatic T cells (TCs) secreting TNF-α, TGFβ, IL-10, and IFN-γ [33,34]; and (7) liver sinusoidal endothelial cells (LSECs) releasing chemokines and cytokines including IFN-γ [35,36].…”

“…Abundant immune cells with their secreted mediators presumably trigger various liver diseases of different etiologies [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]but a firm diagnosis thereof must be ascertained. This also applies to DILI, which is confrontedby multiple alternative causes that potentially confound the diagnosis of DILIin a normal clinical and ambulatory setting [7], a phenomenon known among DILI experts since1990 reports [37,38].…”