March1-dependent modulation of donor MHC II on CD103+ dendritic cells mitigates alloimmunity

Thiago J. Borges, Naoka Murakami, Felipe D. Machado, Ayesha Murshid, Benjamin J. Lang, Rafael L. Lopes, Laura M. Bellan, Mayuko Uehara, Krist H. Antunes, Maria José Pérez-Saéz, Gabriel Birrane, Priscila Vianna, João Ismael B. Gonçalves, Rafael F. Zanin, Jamil Azzi, Reza Abdi, Satoshi Ishido, Jeoung-Sook Shin, Ana Paula D. Souza, Stuart K. Calderwood, Leonardo V. Riella () and Cristina Bonorino ()
Additional contact information
Thiago J. Borges: Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS. Av. Ipiranga
Naoka Murakami: Harvard Medical School
Felipe D. Machado: Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS. Av. Ipiranga
Ayesha Murshid: Harvard Medical School
Benjamin J. Lang: Harvard Medical School
Rafael L. Lopes: Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS. Av. Ipiranga
Laura M. Bellan: Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS. Av. Ipiranga
Mayuko Uehara: Harvard Medical School
Krist H. Antunes: Biomedical Research Institute, PUCRS. Av. Ipiranga
Maria José Pérez-Saéz: Harvard Medical School
Gabriel Birrane: Harvard Medical School
Priscila Vianna: Universidade Federal do Rio Grande do Sul
João Ismael B. Gonçalves: Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS. Av. Ipiranga
Rafael F. Zanin: Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS. Av. Ipiranga
Jamil Azzi: Harvard Medical School
Reza Abdi: Harvard Medical School
Satoshi Ishido: Hyogo College of Medicine
Jeoung-Sook Shin: University of California San Francisco
Ana Paula D. Souza: Harvard Medical School
Stuart K. Calderwood: Harvard Medical School
Leonardo V. Riella: Harvard Medical School
Cristina Bonorino: Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS. Av. Ipiranga

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05572-z

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