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.
Highlights
In transplantation, donor dendritic cells initiate the alloimmune response either by direct interaction with host T cells or by transferring intact donor MHC to host Dendritic cells (DCs)
We found that MHC class II (MHC II) (I-Ab) was present in draining lymph nodes (dLN) from 3 h to day 7 post-transplant (Fig. 1a)
We previously demonstrated that DnaK could modulate DC properties in a pathway involving extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3)[29]
Summary
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. 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 March[1], which ubiquitinates and decreases MHC-II levels. The in situ treatment of donor skin grafts with DnaK prior to transplant induces IL-10 and decreases donor MHC II levels in CD103+ DCs, reducing alloreactive T cell priming and extending graft survival. In human DCs, DnaK induces MARCH1 and downregulates HLA-DR (MHC II) levels in CD141+, but not CD1c+ DCs. We propose that targeting donor CD103+/ CD141+ DCs prior to transplant constitutes a novel approach to reduce immunogenicity of the transplanted allograft upon transplantation
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