Liver Damage Preferentially Results from CD8+ T Cells Triggered by High Affinity Peptide Antigens

Abstract

Little is understood of the anatomical fate of activated T lymphocytes and the consequences they have on the tissues into which they migrate. Previous work has suggested that damaged lymphocytes migrate to the liver. This study compares class I versus class II major histocompatibility complex (MHC)–restricted ovalbumin-specific T cell antigen receptor (TCR) transgenic mice to demonstrate that after in vivo activation with antigen the emergence of CD4−CD8−B220+ T cells occurs more frequently from a CD8+ precursor than from CD4+ T cells. Furthermore, this change in phenotype is conferred only by the high affinity native peptide antigen and not by lower affinity peptide variants. After activation of CD8+ cells with only the high affinity peptide, there is also a dramatically increased number of liver lymphocytes with accompanying extensive hepatocyte damage and elevation of serum aspartate transaminase. This was not observed in mice bearing a class II MHC–restricted TCR. The findings show that CD4−CD8−B220+ T cells preferentially derive from a CD8+ precursor after a high intensity TCR signal. After activation, T cells can migrate to the liver and induce hepatocyte damage, and thereby serve as a model of autoimmune hepatitis.

Virus-Specific CD8+ T Cells in the Liver: Armed and Ready to Kill

“…Early experiments suggesting that the liver might be an "anatomical graveyard" used superantigens and Ag-driven responses in mice transgenic for a given TCR (10,11,(33)(34)(35). However, the unnaturally high proportion of Agspecific cells and/or high-intensity TCR stimulation in these systems does not necessarily reflect what might occur under physiological conditions.…”

Administration of an Antigen at a High Dose Generates Regulatory CD4+ T Cells Expressing CD95 Ligand and Secreting IL-4 in the Liver

“…IHL were prepared following the method described previously with some modifications (25). The portal vein was cannulated with a 27-gauge needle and perfused with 5 ml of PBS, with the inferior vena cava being cut above the liver.…”

Hepatocytes as cytotoxic effector cells can induce cell death by CD95 ligand‐mediated pathway†

“…After birth, the liver is the site of production of immune competent cells, including natural killer (NK), natural killer T (NKT), and extrathymic T cells, 1 elimination of activated cytotoxic T cells (CTL), [2][3][4][5] and synthesis of complement and acute phase proteins. 6 The liver is considered an immunocompetent organ whose contributions toward induction of peripheral immunotolerance and surveillance against pathogens are increasingly recognized.…”