ABSTRACT
CD8 T cells protect the liver against viral infection, but can also cause severe liver damage that may even lead to organ failure. Given the lack of mechanistic insights and specific treatment options in patients with acute fulminant hepatitis, we develop a mouse model reflecting a severe acute virus-induced CD8 T cell-mediated hepatitis. Here we show that antigen-specific CD8 T cells induce liver damage in a perforin-dependent manner, yet liver failure is not caused by effector responses targeting virus-infected hepatocytes alone. Additionally, CD8 T cell mediated elimination of cross-presenting liver sinusoidal endothelial cells causes endothelial damage that leads to a dramatically impaired sinusoidal perfusion and indirectly to hepatocyte death. With the identification of perforin-mediated killing as a critical pathophysiologic mechanism of liver failure and the protective function of a new class of perforin inhibitor, our study opens new potential therapeutic angles for fulminant viral hepatitis.
Subject(s)
Endothelial Cells/drug effects , Hepatitis, Viral, Animal/drug therapy , Liver/drug effects , Pore Forming Cytotoxic Proteins/antagonists & inhibitors , Protective Agents/pharmacology , Sulfonamides/pharmacology , Adenoviridae/genetics , Adenoviridae/immunology , Adenoviridae/pathogenicity , Animals , Antibodies/administration & dosage , CD40 Antigens/antagonists & inhibitors , CD40 Antigens/genetics , CD40 Antigens/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Capillaries/drug effects , Capillaries/virology , Disease Models, Animal , Endothelial Cells/immunology , Endothelial Cells/virology , Gene Expression , Genes, Reporter , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Hepatitis, Viral, Animal/immunology , Hepatitis, Viral, Animal/virology , Hepatocytes/drug effects , Hepatocytes/immunology , Hepatocytes/virology , Humans , Liver/blood supply , Liver/pathology , Liver/virology , Luciferases/genetics , Luciferases/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Ovalbumin/administration & dosage , Poly I-C/administration & dosage , Pore Forming Cytotoxic Proteins/genetics , Pore Forming Cytotoxic Proteins/immunologyABSTRACT
The development of dysfunctional or exhausted T cells is characteristic of immune responses to chronic viral infections and cancer. Exhausted T cells are defined by reduced effector function, sustained upregulation of multiple inhibitory receptors, an altered transcriptional program and perturbations of normal memory development and homeostasis. This review focuses on (a) illustrating milestone discoveries that led to our present understanding of T cell exhaustion, (b) summarizing recent developments in the field, and (c) identifying new challenges for translational research. Exhausted T cells are now recognized as key therapeutic targets in human infections and cancer. Much of our knowledge of the clinically relevant process of exhaustion derives from studies in the mouse model of Lymphocytic choriomeningitis virus (LCMV) infection. Studies using this model have formed the foundation for our understanding of human T cell memory and exhaustion. We will use this example to discuss recent advances in our understanding of T cell exhaustion and illustrate the value of integrated mouse and human studies and will emphasize the benefits of bi-directional mouse-to-human and human-to-mouse research approaches.
