Liver-primed CD8 ⁺ T cells suppress antiviral adaptive immunity through galectin-9-independent T-Cell immunoglobulin and mucin 3 engagement of high-mobility group box 1 in mice

Abstract

The liver is a tolerogenic environment exploited by persistent infections, such as hepatitis B (HBV) and C (HCV) viruses. In a murine model of intravenous hepatotropic adenovirus infection, liver-primed antiviral CD8 ⁺ T cells fail to produce proinflammatory cytokines and do not display cytolytic activity characteristic of effector CD8 ⁺ T cells generated by infection at an extrahepatic, that is, subcutaneous, site. Importantly, liver-generated CD8 ⁺ T cells also appear to have a T-regulatory (T _reg) cell function exemplified by their ability to limit proliferation of antigen-specific T-effector (T _eff) cells in vitro and in vivo via T-cell immunoglobulin and mucin 3 (Tim-3) expressed by the CD8 ⁺ T _reg cells. Regulatory activity did not require recognition of the canonical Tim-3 ligand, galectin-9, but was dependent on CD8 ⁺ T _reg cell-surface Tim-3 binding to the alarmin, high-mobility group box 1 (HMGB-1). Conclusion: Virus-specific Tim-3 ⁺CD8 ⁺ T cells operating through HMGB-1 recognition in the setting of acute and chronic viral infections of the liver may act to dampen hepatic T-cell responses in the liver microenvironment and, as a consequence, limit immune-mediated tissue injury or promote the establishment of persistent infections. (H epatology 2014;59:1351-1365)