CD40Ig treatment results in allograft acceptance mediated by CD8CD45RC T cells, IFN-gamma, and indoleamine 2,3-dioxygenase

J Clin Invest. 2007 Apr;117(4):1096-106. doi: 10.1172/JCI28801.


Treatment with CD40Ig results in indefinite allograft survival in a complete MHC-mismatched heart allograft model in the rat. Here we show that serial second, third, and fourth adoptive transfers of total splenocytes from CD40Ig-treated recipients into secondary recipients led to indefinite donor-specific allograft acceptance. Purification of splenocyte subpopulations from CD40Ig-treated recipients demonstrated that only the adoptively transferred CD8(+)CD45RC(low) subset resulted in donor-specific long-term survival, whereas CD8(+)CD45RC(low) T cells from naive animals did not. Accepted grafts displayed increased indoleamine 2,3-dioxygenase (IDO) expression restricted in the graft to ECs. Coculture of donor ECs with CD8(+)CD45RC(low) T cells purified from CD40Ig-treated animals resulted in donor-specific IDO expression dependent on IFN-gamma. Neutralization of IFN-gamma or IDO triggered acute allograft rejection in both CD40Ig-treated and adoptively transferred recipients. This study demonstrates for what we believe to be the first time that interference in CD40-CD40 ligand (CD40-CD40L) interactions induces allospecific CD8(+) Tregs that maintain allograft survival. CD8(+)CD45RC(low) T cells act through IFN-gamma production, which in turn induces IDO expression by graft ECs. Thus, donor alloantigen-specific CD8(+) Tregs may promote local graft immune privilege through IDO expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Graft Survival / drug effects
  • Graft Survival / immunology
  • Graft Survival / physiology*
  • Heart Transplantation / immunology
  • Heart Transplantation / physiology*
  • Immune Tolerance / drug effects
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / physiology*
  • Interferon-gamma / physiology*
  • Rats
  • Rats, Inbred Lew
  • Recombinant Fusion Proteins / therapeutic use*
  • T-Lymphocytes / immunology*
  • Transplantation, Homologous / immunology


  • CD40Ig protein, recombinant
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Recombinant Fusion Proteins
  • Interferon-gamma