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

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. Using a mouse skin transplant model combining anti-CD3 treatment with autologous tolerogenic dendritic cell infusion, the authors demonstrate the importance of antigen cross-presentation to prolong allograft survival mediated by CD8+ regulatory T cells by characterizing a novel cation channel, Tmem176b, that participates in the fine-tuning of phagosomal pH in dendritic cells. See editorial by Morelli and Thomson on page 989.