Autologous Dendritic Cells Prolong Allograft Survival Through Tmem176b-Dependent Antigen Cross-Presentation

M Segovia 1, 2 C. Louvet 1, 2 P. Charnet 3 A. Savina 4 G. Tilly 1, 2 L. Gautreau 1, 2 L. Carretero-Iglesia 1, 2 G. Beriou 1, 2 I. Cebrian 4 T. Cens 3 L. Hepburn 5 E. Chiffoleau 1, 2 R Floto 5 I. Anegon 1, 2 S. Amigorena 4 M. Hill 1, 2 M. Cuturi 1, 2
1 U1064 Inserm - CRTI - Centre de Recherche en Transplantation et Immunologie
2 ITUN - Institut de transplantation urologie-néphrologie
3 CRBM - Centre de recherche en Biologie Cellulaire
4 U932 - Immunité et cancer
5 Department of Medicine [Cambridge, U.K.]
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
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M Segovia, C. Louvet, P. Charnet, A. Savina, G. Tilly, et al.. Autologous Dendritic Cells Prolong Allograft Survival Through Tmem176b-Dependent Antigen Cross-Presentation. American Journal of Transplantation, Wiley, 2014, 14 (5), pp.1021-1031. ⟨10.1111/ajt.12708⟩. ⟨inserm-02167834⟩

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