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

TLDR

Toll‑like receptors are germline‑encoded innate immune receptors on antigen‑presenting cells, yet their role in solid‑organ transplantation remains unknown. The study aimed to determine whether TLR signaling contributes to allograft rejection. Using a skin allograft model in mice lacking the universal TLR adaptor MyD88, the authors investigated this question. Allograft rejection of minor antigen‑mismatched grafts failed in MyD88‑deficient mice due to reduced mature dendritic cells in draining lymph nodes, leading to impaired anti‑graft T‑cell and Th1 responses, thereby demonstrating that TLR activation initiates adaptive alloimmunity in transplantation.

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.