PD-L1 Signal on Liver Dendritic Cells Is Critical for Foxp3+CD4+CD25+ Treg and Liver Tolerance Induction in Mice

Abstract

Allogeneic liver transplantation induces spontaneous tolerance in mice without a requirement for immunosuppression. The underling mechanisms remain unclear. Our recent studies indicated that Foxp3+CD25+CD4+ regulatory T (Treg) cells play an important role in the induction of spontaneous transplant tolerance. How Treg cells are induced and their functional mechanisms to regulate the response remain undefined. In this study, we employed a mouse liver transplant model using PD-L1-/-, and Flt3L-/- mice to critically examine the role of liver dendritic cells (DCs) and the PD-L1 signal in Treg induction. Our results showed that liver DCs, which expressed a great number of PD-L1 molecules, induced more Foxp3+CD25+CD4+ Treg in vitro upon coculture with allogeneic CD4 T cells compared with spleen DCs. The DCs from PD-L1-deficient mice failed to expand Foxp3+CD25+CD4+ Treg in vitro. Adoptive transfer of Foxp3+CD25+CD4+Treg expanded from liver DCs prolonged heart allograft survival significantly greater than spleen cell controls. Moreover, liver grafts from Flt3L-/- and PD-L1-/- mice were rejected acutely in C3H recipients. Immunohistochemistry revealed reduced Foxp3+ cells and significantly increased IL-2, IL-10, and IFN-γ producing elements in the liver grafts and recipient spleens of Flt3L-/- and PD-L1-/- donors. In conclusion, liver DCs play a critical role in the induction of Foxp3+CD25+CD4+ Treg, which may mediate spontaneous acceptance of MHC-mismatched liver allografts in mice. The effects of DCs on Foxp3+CD25+CD4+ Treg induction and expansion appear to depend on the PD-L1 signal.