Inhibition of TLR4 signaling prolongs Treg-dependent murine islet allograft survival

Toll-like receptors (TLRs) provide an important link between innate and adaptive immune system. We hypothesized that the recognition of endogenous TLR4 ligands is occurring at the time of transplantation, and these innate signals drive the inflammation and affect alloimmune responses. We confirmed that early after transplantation of allogenic islets, transcripts for TLR4 as well as potential ligands were released or up-regulated. In an allogenic islet transplantation model, genetic disruption of TLR4 on donor islets had no effect on allograft survival, whereas TLR4 deficiency in recipients lead to prolonged graft survival. Low dose rapamycin-treatment of TLR4(-/-) recipients induced permanent engraftment of 45% islet graft (p=0.005) compared to WT recipients. This prolonged graft survival was dependent on the presence of CD4(+)CD25(+)Foxp3(+) Treg. Naïve CD4(+)CD25(-) T cells cultured with the TLR4 ligand lipopolysaccharide showed enhanced IL-4, IL-6, IL-17, IFN gamma secretion and inhibited TGFbeta induced Foxp3(+)Treg generation. Thus, inhibition of recipient TLR4 activation at the time of transplantation decreases proinflammatory signals and allows Treg generation.