Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection
Daniel R. Goldstein, … , Shizuo Akira, Fadi G. Lakkis
Daniel R. Goldstein, … , Shizuo Akira, Fadi G. Lakkis
Published May 15, 2003
Citation Information: J Clin Invest. 2003;111(10):1571-1578. https://doi.org/10.1172/JCI17573.
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Article

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.

Authors

Daniel R. Goldstein, Bethany M. Tesar, Shizuo Akira, Fadi G. Lakkis

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MyD88–/– recipients have a reduced number of mature and immature DCs in ...
MyD88–/– recipients have a reduced number of mature and immature DCs in lymph nodes draining the allografts. (a) Despite having similar numbers of mature (CD40+CD11c+, CD80+CD11c+, and CD86+CD11c+) DCs on day 0, MyD88–/– recipients were unable to increase numbers of mature DCs on days 7 and 14, whereas WT counterparts had stable numbers of mature DCs during the first week that increased nearly fivefold by day 14 (P = 0.0001 vs. MyD88–/–). (b) Immature (CD40–CD11c+, CD80–CD11c+, and CD86–CD11c+) DCs failed to accumulate in the draining lymph nodes of allografts of MyD88–/– recipients of MyD88–/– male grafts on days 0, 7, and 14 after transplantation (on day 14, MyD88+/+ CD40–CD11c+ vs. MyD88–/– CD40–CD11c+P = 0.0002; MyD88+/+ CD80–CD11c+ vs. MyD88–/– CD80–CD11c+P < 0.01; MyD88+/+ CD86–CD11c+ vs. MyD88–/– CD86–CD11c+P < 0.01). (c) Analysis of the number of mature DCs in the draining lymph nodes in different transplant combinations on day 14 after transplantation. The presence of WT APCs in either the donor or the recipient partially restored the number of mature DCs present in the draining lymph nodes when compared with the MyD88+/+ → MyD88+/+ transplant combination. *P < 0.009 vs. MyD88+/+ → MyD88+/+, P < 0.02 vs. MyD88–/– → MyD88–/–; **P < 0.02 vs. MyD88+/+ → MyD88+/+, P < 0.006 vs. MyD88–/– → MyD88–/–.