小鼠肝脏非实质细胞在诱导Foxp3+CD4+CD25+调节性T细胞及肝移植免疫耐受中起重要作用

Our recent studies have demonstrated that Foxp3+CD25+CD4+ regulatory T cells (Treg) contribute significantly to liver transplant tolerance induction. It is largely unclear how Treg are induced and how these cells interplay in the regulation of liver transplant tolerance. Here, we attempted to expand the number of Treg in vitro by coculture of liver nonparenchymal cells (NPCs) or dendritic cells (DCs) with allogeneic CD4 T cells, and assessed their function by adoptive transfer to heart allograft recipients. We used Flt3 ligand (FL) mutation mice, which have severe reduction in all types of DCs, to examine the role of liver DCs in liver transplant tolerance in vivo after liver transplantation. Our results showed that liver NPCs, in particular DCs, induced a greater number of Foxp3+ Treg than did spleen cells (SCs) and spleen DCs. Adoptive transfer of the CD25+CD4+ T cells generated from liver NPCs or DCs prolonged heart allograft survival at a significantly higher level than the cells expanded by SCs or spleen DCs. The DCs which isolated from PD-L1-/- mice could not generate Treg in vitro. Moreover, the liver grafts from FL-/- or PD-L1-/- mice were rejected acutely in the C3H recipients and associated with reduction of Foxp3+ cells in the liver grafts and recipient spleens from FL-/- donors. Thus, liver NPCs, in particular DCs, play a critical role in the induction of Treg, which underpin spontaneous acceptance of MHC-mismatched liver allografts in mice.