Ig-stimulated T-cells. Administration of soluble VSIG4.Ig to wildtype mice prevented CIH development and prolonged this website the survival of mice with established CIH. Conclusion: Collectively, our results suggest that VSIG4+ KCs play a critical role in the induction and maintenance

of liver T- and NKT-cell tolerance, and that modulation of the VSIG4 pathway using a VSIG4.Ig fusion protein may provide useful immunological therapies against immune-mediated liver injury including autoimmune hepatitis. (HEPATOLOGY 2012;56:1838–1848) Despite the risk of immune activation by continuous exposure to potential antigens, the liver avoids overactivation of the innate and adaptive immune responses by inducing tolerance.1, 2 Many studies have investigated the molecular and cellular selleck compound basis of liver tolerance. Initial studies focused on identifying tolerance-inducing soluble factors from liver nonparenchymal cells, including hepatic stellate cells (HSCs) and liver-resident antigen-presenting cells (APCs), such as liver sinusoid endothelial cells (LSECs), hepatic dendritic cells (DCs),

and Kupffer cells (KCs).3 Among them, KCs are believed to induce liver tolerance by producing an immunosuppressive cytokine, interleukin (IL)-10, and immunosuppressive metabolites including nitric oxide, prostaglandin E2 (PGE2), and 15-deoxy-delta 12,14-PGJ2 (15d-PGJ2).3–6 Alternative mechanisms for liver tolerance have also been suggested. KCs prime CD4+ T-cells to be converted to regulatory T cells (Tregs) with a CD25low FoxP3neg phenotype NADPH-cytochrome-c2 reductase that can inhibit the proliferation of naïve CD4+ T-cells.7, 8 The functional significance of B7-H1 (PD-L1 or CD274), a coinhibitory ligand, in liver tolerance was demonstrated by showing that B7-H1-expressing KCs directly suppress T-cell proliferation and cytokine production by way of the B7-H1:PD-1 pathway.9 These results suggest that coinhibitory ligands in the liver microenvironment are important for regulating local immune responses. Despite the increasing

number of coinhibitory ligands that play negative roles in T-cell responses, few studies have focused on the cellular and molecular mechanisms of liver tolerance mediated by these coinhibitory ligands. Recently, V-set and Ig domain-containing 4 (VSIG4, also referred to as CRIg or Z39Ig) was identified as a B7-related immunoglobulin superfamily member that is exclusively expressed on tissue-resident macrophages and particularly on liver KCs.10 VSIG4 is a complement receptor for C3b and iC3b, and its binding to the convertase subunit C3b interferes with C5 binding to C3b, thus blocking the alternative complement pathway and subsequent suppression of inflammatory responses.10 VSIG4 also acts as a coinhibitory ligand that negatively modulates adaptive immunity.