TLR1/2 ligand-stimulated mouse liver endothelial cells secrete IL-12 and trigger CD8+ T cell immunity in vitro

• Published in: The Journal of immunology (1950) 2013-12, Vol.191 (12), p.6178-6190
• Main Authors: Liu, Jia, Jiang, Min, Ma, Zhiyong, Dietze, Kirsten K, Zelinskyy, Gennadiy, Yang, Dongliang, Dittmer, Ulf, Schlaak, Joerg F, Roggendorf, Michael, Lu, Mengji
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Apoptosis; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - biosynthesis; B7-H1 Antigen - genetics; CD8-Positive T-Lymphocytes - immunology; Endothelial Cells - drug effects; Endothelial Cells - immunology; Endothelial Cells - metabolism; Endothelial Cells - secretion; Female; Friend murine leukemia virus - immunology; Friend murine leukemia virus - physiology; Gene Expression Regulation - drug effects; Immune Tolerance; Immunity, Cellular; In Vitro Techniques; Interleukin-12 - biosynthesis; Interleukin-12 - genetics; Interleukin-12 - secretion; Ligands; Lipopeptides - pharmacology; Liver - cytology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Toll-Like Receptor 2 - agonists; Toll-Like Receptors - agonists; Vaccines, DNA; Virus Replication
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1301262

Liver sinusoidal endothelial cells (LSECs) are unique organ-resident APCs capable of Ag cross-presentation and subsequent tolerization of naive CD8(+) T cells. Under certain conditions, LSECs can switch from a tolerogenic to an immunogenic state and promote the development of T cell immunity. However, little is known about the mechanisms of LSECs to induce T cell immunity. In this study, we investigated whether functional maturation of LSECs can be achieved by TLR ligand stimulation and elucidated the mechanisms involved in LSEC-induced T cell immunity. We demonstrate that pretreatment of LSECs with palmitoyl-3-cysteine-serine-lysine-4 (P3C; TLR1/2 ligand) but not poly(I:C) (TLR3 ligand) or LPS (TLR4 ligand) reverted their suppressive properties to induce T cell immunity. Importantly, P3C stimulation caused functional maturation of Ag-presenting LSECs and enabled them to activate virus-specific CD8(+) T cells. The LSEC-mediated CD8(+) T cell immunity was initiated by soluble mediators, one of which was IL-12 secreted at a low but sustained level after P3C stimulation. P3C stimulation did not induce programmed death ligand 1 expression on LSECs, thereby favoring T cell proliferation and activation instead of suppression. Our data suggest that LSECs undergo maturation exclusively in response to TLR1/2 ligand stimulation and that the immunological status of LSECs was dependent upon the balance between programmed death ligand 1 and IL-12 expression. These results have implications for our understanding of liver-specific tolerance and autoimmunity and for the development of strategies to overcome T cell tolerance in situations such as chronic viral liver infections or liver cancer.