Synopses & Reviews
Immune activation via Toll-like receptors (TLRs) has recently been identified as an important barrier to the induction of donor-specific transplantation tolerance, but the exact mechanisms underlying this barrier remain unclear. To better understand how TLR ligation interferes with the induction of donor-specific tolerance, we used complementary murine models of skin and cardiac transplantation in which prolonged allograft acceptance is either spontaneous or pharmacologically induced with anti-CD154 mAb and rapamycin. In each model, we found that prolonged allograft survival requires the presence of natural CD4+Foxp3+ regulatory T cells, and that TLR ligation prevents graft acceptance both by interfering with natural Treg function and by promoting the differentiation of Th1 effector T cells in vivo. We further demonstrate that TLR ligands mediate these effects in the absence of IL-6, and that Th17 cells do not participate in the abrogation of tolerance by TLR ligands. Finally, in light of our observation that rapamycin induces CD4+Foxp3+ adaptive Treg conversion from alloreactive Foxp3-effector T cells, we investigated the role of these cells in the tolerance process and conclude that natural Tregs are the dominant Foxp3+ regulatory T cell subset that establishes immunoregulation in animals treated with costimulatory blockade and rapamycin. Altogether, these data suggest that TLR signals do not prevent prolonged graft acceptance by preventing alloantigen-specific adaptive Treg differentiation. Instead, graft destruction results from the ability of TLR ligands to promote Th1 differentiation and interfere with immunoregulation established by alloreactive natural CD4+Foxp3+ Tregs.