Tolerogenic Donor-Derived Dendritic Cells Risk Sensitization In Vivo owing to Processing and Presentation by Recipient APCs

J Immunol. 2013 May 1;190(9):4848-60. doi: 10.4049/jimmunol.1200870. Epub 2013 Mar 27.


Modification of allogeneic dendritic cells (DCs) through drug treatment results in DCs with in vitro hallmarks of tolerogenicity. Despite these observations, using murine MHC-mismatched skin and heart transplant models, donor-derived drug-modified DCs not only failed to induce tolerance but also accelerated graft rejection. The latter was inhibited by injecting the recipient with anti-CD8 Ab, which removed both CD8(+) T cells and CD8(+) DCs. The discrepancy between in vitro and in vivo data could be explained, partly, by the presentation of drug-modified donor DC MHC alloantigens by recipient APCs and activation of recipient T cells with indirect allospecificity, leading to the induction of alloantibodies. Furthermore, allogeneic MHC molecules expressed by drug-treated DCs were rapidly processed and presented in peptide form by recipient APCs in vivo within hours of DC injection. Using TCR-transgenic T cells, Ag presentation of injected OVA-pulsed DCs was detectable for ≤ 3 d, whereas indirect presentation of MHC alloantigen by recipient APCs led to activation of T cells within 14 h and was partially inhibited by reducing the numbers of CD8(+) DCs in vivo. In support of this observation when mice lacking CD8(+) DCs were pretreated with drug-modified DCs prior to transplantation, skin graft rejection kinetics were similar to those in non-DC-treated controls. Of interest, when the same mice were treated with anti-CD40L blockade plus drug-modified DCs, skin graft survival was prolonged, suggesting endogenous DCs were responsible for T cell priming. Altogether, these findings highlight the risks and limitations of negative vaccination using alloantigen-bearing "tolerogenic" DCs.

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD40 Ligand / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Dendritic Cells / immunology*
  • Forkhead Transcription Factors / immunology
  • Graft Rejection / immunology
  • Heart Transplantation / immunology
  • Immune Tolerance / immunology*
  • Isoantigens / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Receptors, Antigen, T-Cell / immunology
  • Skin Transplantation / immunology
  • Tissue Donors
  • Transplantation


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Isoantigens
  • Receptors, Antigen, T-Cell
  • CD40 Ligand