| First Author | Segovia M | Year | 2014 |
| Journal | Am J Transplant | Volume | 14 |
| Issue | 5 | Pages | 1021-1031 |
| PubMed ID | 24731243 | Mgi Jnum | J:263140 |
| Mgi Id | MGI:6164435 | Doi | 10.1111/ajt.12708 |
| Citation | Segovia M, et al. (2014) Autologous dendritic cells prolong allograft survival through Tmem176b-dependent antigen cross-presentation. Am J Transplant 14(5):1021-1031 |
| abstractText | 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. |
