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

M Segovia; C. Louvet; P. Charnet; A. Savina; G. Tilly; L. Gautreau; L. Carretero-Iglesia; G. Beriou; I. Cebrian; T. Cens; L. Hepburn; E. Chiffoleau; R Floto; I. Anegon; S. Amigorena; M. Hill; M. Cuturi

doi:10.1111/ajt.12708

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

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Human health and pathology

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https://www.hal.inserm.fr/inserm-02167834
Contributor : Ana Paula Dutra Azevedo <>
Submitted on : Friday, June 28, 2019 - 11:11:55 AM
Last modification on : Friday, July 5, 2019 - 1:18:25 AM

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