학술논문
March1-dependent modulation of donor MHC II on CD103+ dendritic cells mitigates alloimmunity.
Document Type
article
Author
Borges, Thiago J; Murakami, Naoka; Machado, Felipe D; Murshid, Ayesha; Lang, Benjamin J; Lopes, Rafael L; Bellan, Laura M; Uehara, Mayuko; Antunes, Krist H; Pérez-Saéz, Maria José; Birrane, Gabriel; Vianna, Priscila; Gonçalves, João Ismael B; Zanin, Rafael F; Azzi, Jamil; Abdi, Reza; Ishido, Satoshi; Shin, Jeoung-Sook; Souza, Ana Paula D; Calderwood, Stuart K; Riella, Leonardo V; Bonorino, Cristina
Source
Nature communications. 9(1)
Subject
Language
Abstract
In transplantation, donor dendritic cells (do-DCs) initiate the alloimmune response either by direct interaction with host T cells or by transferring intact donor MHC to host DCs. However, how do-DCs can be targeted for improving allograft survival is still unclear. Here we show CD103+ DCs are the major do-DC subset involved in the acute rejection of murine skin transplants. In the absence of CD103+ do-DCs, less donor MHC-II is carried to host lymph nodes, fewer allogenic T cells are primed and allograft survival is prolonged. Incubation of skin grafts with the anti-inflammatory mycobacterial protein DnaK reduces donor MHC-II on CD103+DCs and prolongs graft survival. This effect is mediated through IL-10-induced March1, which ubiquitinates and decreases MHC-II levels. Importantly, in vitro pre-treatment of human DCs with DnaK reduces their ability to prime alloreactive T cells. Our findings demonstrate a novel therapeutic approach to dampen alloimmunity by targeting donor MHC-II on CD103+DCs.