Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection

Abstract

The Toll-like receptors (TLRs) are recently discovered germline-encoded receptors on APCs that are critically important in innate immune recognition of microbial pathogens. However, their role in solid-organ transplantation is unknown. To explore this role, we employed a skin allograft model using mice with targeted deletion of the universal TLR signal adaptor protein, MyD88. We report that minor antigen-mismatched (HY-mismatched) allograft rejection cannot occur in the absence of MyD88 signaling. Furthermore, we show that the inability to reject these allografts results from a reduced number of mature DCs in draining lymph nodes, leading to impaired generation of anti-graft-reactive T cells and impaired Th1 immunity. Hence, this work demonstrates that TLRs can be activated in a transplant setting and not solely by infections. These results link innate immunity to the initiation of the adaptive alloimmune response.

Role of Toll-Like Receptor–Driven Innate Immunity in Thoracic Organ Transplantation

“…47 Thus, these data provide evidence that innate immune signaling can lead to the initiation of an adaptive alloimmune response.…”

“…47,49 However, TH2 immunity is not diminished in the absence of MyD88 signaling. 47,49 Unresolved questions include the nature of the innate immune ligands, whether MyD88-independent alloimmunity is dependent on TH2 immune function, and whether alternate TLR signal adaptors are important. Our results revealed that, in the absence of MyD88, female MyD88 -/-recipients could not reject male MyD88 -/-male allografts (8 of 9 recipients with Ͼ100-day median graft survival vs MyD88 ϩ/ϩ littermate controls that rejected their allografts by Day 25 posttransplant).…”

“…Because IL-1 and IL-18 also signal via MyD88, and both are synthesized in an inactive form that requires cleavage via caspase-1, we used mice deficient in caspase-1 (designated ICE -/-) to control for TLR-independent, IL-1/IL-18 -driven MyD88 signaling. 47 This leads to TH1 immunity against the allograft, 47,49 which is critical for the rejection of minor-mismatched allografts but not fully MHC-mismatched allografts. 47,49 However, TH2 immunity is not diminished in the absence of MyD88 signaling.…”

“…47 This leads to TH1 immunity against the allograft, 47,49 which is critical for the rejection of minor-mismatched allografts but not fully MHC-mismatched allografts. 47,49 However, TH2 immunity is not diminished in the absence of MyD88 signaling. 47,49 Unresolved questions include the nature of the innate immune ligands, whether MyD88-independent alloimmunity is dependent on TH2 immune function, and whether alternate TLR signal adaptors are important.…”

Toll-like Receptor and Cytokine Gene Expression in the Early Phase of Human Lung Transplantation

“…21 TLRs and their intracellular signal transduction pathways have been proposed to be important for minor antigen-mismatch allograft survival. 22 In addition, TLR4 polymorphism has been reported to be related to outcome of lung graft rejection. 23,24 The importance of TLRs and innate immunity in organ transplantation has been highlighted by several review articles and conferences.…”