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

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. (Hepatology 2014;59:1351-1365)