Autologous dendritic cells prolong allograft survival through Tmem176b-dependent antigen cross-presentation

Am J Transplant. 2014 May;14(5):1021-1031. doi: 10.1111/ajt.12708. Epub 2014 Apr 14.


The administration of autologous (recipient-derived) tolerogenic dendritic cells (ATDCs) is under clinical evaluation. However, the molecular mechanisms by which these cells prolong graft survival in a donor-specific manner is unknown. Here, we tested mouse ATDCs for their therapeutic potential in a skin transplantation model. ATDC injection in combination with anti-CD3 treatment induced the accumulation of CD8(+) CD11c(+) T cells and significantly prolonged allograft survival. TMEM176B is an intracellular protein expressed in ATDCs and initially identified in allograft tolerance. We show that Tmem176b(-/-) ATDCs completely failed to trigger both phenomena but recovered their effect when loaded with donor peptides before injection. These results strongly suggested that ATDCs require TMEM176B to cross-present antigens in a tolerogenic fashion. In agreement with this, Tmem176b(-/-) ATDCs specifically failed to cross-present male antigens or ovalbumin to CD8(+) T cells. Finally, we observed that a Tmem176b-dependent cation current controls phagosomal pH, a critical parameter in cross-presentation. Thus, ATDCs require TMEM176B to cross-present donor antigens to induce donor-specific CD8(+) CD11c(+) T cells with regulatory properties and prolong graft survival.

Keywords: Autologous dendritic cells; cellular therapy; cross-presentation; ion channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allografts
  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Antigen Presentation / immunology*
  • CD3 Complex / immunology*
  • CD8-Positive T-Lymphocytes / immunology
  • Cross-Priming
  • Dendritic Cells / immunology*
  • Electrophysiology
  • Endocytosis / physiology
  • Female
  • Flow Cytometry
  • Graft Survival / physiology*
  • Immune Tolerance
  • Male
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phagocytosis / physiology
  • Skin Transplantation*


  • Antibodies, Monoclonal
  • CD3 Complex
  • Membrane Proteins
  • Tmem176B protein, mouse