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

Nature Communications
Thiago J BorgesCristina Bonorino

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.

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Citations

Oct 9, 2019·Biology Letters·Arseny DubinLars Martin Jakt
Nov 6, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Tawanda ZiningaAddmore Shonhai
Aug 14, 2019·Frontiers in Immunology·Heng LinHong-Bing Shu
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Feb 6, 2022·Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico·L LiuS Liu

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Methods Mentioned

BETA
ubiquitination
flow cytometry
confocal microscopy
PCR
Protein Assay
density gradient centrifugation
FACS
RNA Assay
Assay
immunoprecipitation

Software Mentioned

BioHeat
BD FACSDiva
Tree
Prism5
Graphpad
GenScript
Cytobank
Flowjo

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