Critical Role of the Toll-like Receptor Signal Adaptor Protein MyD88 in Acute Allograft Rejection

J Clin Invest. 2003 May;111(10):1571-8. doi: 10.1172/JCI17573.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Disease
  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antigens, CD / immunology
  • Antigens, CD / metabolism
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / immunology
  • Antigens, Differentiation / physiology*
  • Cell Count
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology
  • Drosophila Proteins*
  • Female
  • Graft Rejection / genetics
  • Graft Rejection / immunology*
  • H-Y Antigen / immunology
  • Homozygote
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology
  • Interferon-gamma / metabolism
  • Interleukin-4 / metabolism
  • Male
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Mutant Strains
  • Myeloid Differentiation Factor 88
  • Receptors, Cell Surface / metabolism*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / physiology*
  • Skin Transplantation / immunology
  • T-Lymphocytes / immunology
  • Th1 Cells / immunology
  • Th2 Cells / immunology
  • Toll-Like Receptors
  • Transplantation Tolerance / immunology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • Antigens, Differentiation
  • Drosophila Proteins
  • H-Y Antigen
  • Membrane Glycoproteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Toll-Like Receptors
  • Interleukin-4
  • Interferon-gamma