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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

1
ITUN, INSERM UMR_S 1064, Center for Research in Transplantation and Immunology, Nantes, France.
2
CRBM, CNRS UMR 5237, Montpellier, France.
3
Institut Curie, Paris, France.
4
INSERM U932, Paris, France.
5
Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
#
Contributed equally

Abstract

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

PMID:
24731243
PMCID:
PMC4629416
DOI:
10.1111/ajt.12708
[Indexed for MEDLINE]
Free PMC Article

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