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

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

Author information

ITUN, INSERM UMR_S 1064, Center for Research in Transplantation and Immunology, Nantes, France.
CRBM, CNRS UMR 5237, Montpellier, France.
Institut Curie, Paris, France.
INSERM U932, Paris, France.
Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
Contributed equally


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.


Autologous dendritic cells; cellular therapy; cross-presentation; ion channel

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