In vivo expansion of two distinct dendritic cells in mouse livers and its impact on liver immune regulation.
Liver transplant tolerance in pigs, rats, and mice has been disclosed for decades, but the underlying mechanisms are not completely understood. Accumulating data indicate that residing dendritic cells (DC) are important in determining direction of immune responses in the liver. However, our knowledge remains very limited due to the difficulties in obtaining sufficient liver DC. Most of the previous studies were dependent on DC propagated in vitro with growth factors and cytokines. In this study, we adopted an approach to transfect genes into the mouse liver by tail vein injection of plasmid DNA. Transfection with plasmid granulocyte-macrophage colony-stimulating factor markedly expanded liver CD11c(+) DC mainly located in portal regions, while liver B220(+) DC were dramatically generated after injection with plasmid interleukin (IL)-3/CD40L largely present in the lobules. Although both were phenotypically mature and strong T-cell stimulators, CD11c(+)DC induced potent T-cell response while B220(+)DC induced T-cell hyporesponsiveness. Administration of CD11c(+)DC accelerated cardiac allograft rejection, while B220(+)DC significantly prolonged graft survival. This hyporesponsiveness is not due to inhibition of DC/T-cell interaction, but rather through an active process of stimulating T-cell apoptosis. Compared to B220(+) DC that expressed messenger RNA of (TLR) 1, 2, 6, 7, and 9, CD11c(+)DC expressed all TLR 1 to 9. TLR 9 ligation stimulated very high IL-12 in CD11c(+) DC, but high IL-10 and no IL-12 in B220(+) DC. In conclusion, through these mechanisms, liver DC may be actively involved in immune regulation in the liver.
Wang
Yalan
Y
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
Zheng
Ning
N
Lu
Zhengbin
Z
Wu
Wenhan
W
Wang
Lianfu
L
Nakao
Atsunori
A
Lotze
Michael T
MT
Langer
Carrie E
CE
Fung
John J
JJ
Qian
Shiguang
S
Lu
Lina
L
D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D039481:CD11b Antigen / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D039521:CD11c Antigen / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology*; D018014:Gene Transfer Techniques; D006085:Graft Survival / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D016027:Heart Transplantation / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D037181:Lectins, C-Type / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D015778:Minor Histocompatibility Antigens; D010641:Phenotype; D010957:Plasmids / Q000235:genetics; D011956:Receptors, Cell Surface / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D023001:Transplantation Tolerance / Q000276:immunology*
D015703:Antigens, CD; D039481:CD11b Antigen; D039521:CD11c Antigen; C093569:DEC-205 receptor; D007378:Interleukins; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D023201:CD40 Ligand; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017493:Leukocyte Common Antigens