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- Title
March1-dependent modulation of donor MHC II on CD103<sup>+</sup> dendritic cells mitigates alloimmunity.
- Authors
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.
- 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. Donor-derived dendritic cells (do-DC) in the graft can contribute to the induction of alloimmunity and tissue rejection, but how do-DC can be targeted for improving graft survival is unclear. Here the authors show that reducing MHC-II expression on do-DCs by DnaK pre-treatment can decrease the priming of alloimmunity and prolong graft survival in mouse models.
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-05572-z