Mast Cells Condition Dendritic Cells to Mediate Allograft Tolerance

SummaryPeripheral tolerance orchestrated by regulatory T cells, dendritic cells (DCs), and mast cells (MCs) has been studied in several models including skin allograft tolerance. We now define a role for MCs in controlling DC behavior (“conditioning”) to facilitate tolerance. Under tolerant conditions, we show that MCs mediated a marked increase in tumor necrosis factor (TNFα)-dependent accumulation of graft-derived DCs in the dLN compared to nontolerant conditions. This increase of DCs in the dLN is due to the local production of granulocyte macrophage colony-stimulating factor (GM-CSF) by MCs that induces a survival advantage of graft-derived DCs. DCs that migrated to the dLN from the tolerant allograft were tolerogenic; i.e., they dominantly suppress T cell responses and control regional immunity. This study underscores the importance of MCs in conditioning DCs to mediate peripheral tolerance and shows a functional impact of peripherally produced TNFα and GM-CSF on the migration and function of tolerogenic DCs.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (241 K)Download as PowerPoint slideHighlights► TNF and MCs are required for optimal DC migration to maintain peripheral tolerance ► Graft dLN DCs are only suppressive when both antigen and DC are graft derived ► Regional tolerance is maintained due to a survival advantage of graft-derived DCs ► Graft-resident MCs produce GM-CSF inducing an antiapoptotic program in graft DCs