title: Autologous dendritic cells prolong allograft survival through Tmem176b-dependent antigen cross-presentation.
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.
authors.affiliation: ITUN, INSERM UMR_S 1064, Center for Research in Transplantation and Immunology, Nantes, France.
authors.forename: M
authors.initials: M
authors.lastname: Segovia
authors.affiliation: ITUN, INSERM UMR_S 1064, Center for Research in Transplantation and Immunology, Nantes, France.
authors.forename: C
authors.initials: C
authors.lastname: Louvet
authors.affiliation: CRBM, CNRS UMR 5237, Montpellier, France.
authors.forename: P
authors.initials: P
authors.lastname: Charnet
authors.affiliation: Institut Curie, Paris, France.|INSERM U932, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Savina
authors.affiliation: ITUN, INSERM UMR_S 1064, Center for Research in Transplantation and Immunology, Nantes, France.
authors.forename: G
authors.initials: G
authors.lastname: Tilly
authors.affiliation: ITUN, INSERM UMR_S 1064, Center for Research in Transplantation and Immunology, Nantes, France.
authors.forename: L
authors.initials: L
authors.lastname: Gautreau
authors.affiliation: ITUN, INSERM UMR_S 1064, Center for Research in Transplantation and Immunology, Nantes, France.
authors.forename: L
authors.initials: L
authors.lastname: Carretero-Iglesia
authors.affiliation: ITUN, INSERM UMR_S 1064, Center for Research in Transplantation and Immunology, Nantes, France.
authors.forename: G
authors.initials: G
authors.lastname: Beriou
authors.affiliation: Institut Curie, Paris, France.|INSERM U932, Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Cebrian
authors.affiliation: CRBM, CNRS UMR 5237, Montpellier, France.
authors.forename: T
authors.initials: T
authors.lastname: Cens
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: L
authors.initials: L
authors.lastname: Hepburn
authors.affiliation: ITUN, INSERM UMR_S 1064, Center for Research in Transplantation and Immunology, Nantes, France.
authors.forename: E
authors.initials: E
authors.lastname: Chiffoleau
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: R A
authors.initials: RA
authors.lastname: Floto
authors.affiliation: ITUN, INSERM UMR_S 1064, Center for Research in Transplantation and Immunology, Nantes, France.
authors.forename: I
authors.initials: I
authors.lastname: Anegon
authors.affiliation: Institut Curie, Paris, France.|INSERM U932, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Amigorena
authors.affiliation: ITUN, INSERM UMR_S 1064, Center for Research in Transplantation and Immunology, Nantes, France.
authors.forename: M
authors.initials: M
authors.lastname: Hill
authors.affiliation: ITUN, INSERM UMR_S 1064, Center for Research in Transplantation and Immunology, Nantes, France.
authors.forename: M C
authors.initials: MC
authors.lastname: Cuturi
mesh_terms: D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017951:Antigen Presentation / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045142:Cross-Priming; D003713:Dendritic Cells / Q000276:immunology*; D004594:Electrophysiology; D004705:Endocytosis / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D006085:Graft Survival / Q000502:physiology*; D007108:Immune Tolerance; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis / Q000502:physiology; D016038:Skin Transplantation
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D008565:Membrane Proteins; C552366:Tmem176B protein, mouse
keywords: Autologous dendritic cells; cellular therapy; cross-presentation; ion channel
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