TLR1/2 ligand-stimulated mouse liver endothelial cells secrete IL-12 and trigger CD8+ T cell immunity in vitro.
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.
Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, 45122 Essen, Germany;
Jia
J
Liu
Min
M
Jiang
Zhiyong
Z
Ma
Kirsten K
KK
Dietze
Gennadiy
G
Zelinskyy
Dongliang
D
Yang
Ulf
U
Dittmer
Joerg F
JF
Schlaak
Michael
M
Roggendorf
Mengji
M
Lu
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D005260:Female; D005622:Friend murine leukemia virus / Q000276:immunology / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D007108:Immune Tolerance; D007111:Immunity, Cellular; D066298:In Vitro Techniques; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D055666:Lipopeptides / Q000494:pharmacology*; D008099:Liver / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051195:Toll-Like Receptor 2 / Q000819:agonists*; D051193:Toll-Like Receptors / Q000819:agonists*; D019444:Vaccines, DNA; D014779:Virus Replication
D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008024:Ligands; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; C482903:Tlr11 protein, mouse; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D019444:Vaccines, DNA; D018664:Interleukin-12