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Keywords:

  • DAP12;
  • dendritic cells;
  • liver transplant;
  • T cells;
  • tolerance

Liver interstitial dendritic cells (DC) have been implicated in immune regulation and tolerance induction. We found that the transmembrane immuno-adaptor DNAX-activating protein of 12 kDa (DAP12) negatively regulated conventional liver myeloid (m) DC maturation and their in vivo migratory and T cell allostimulatory ability. Livers were transplanted from C57BL/6(H2b) (B6) WT or DAP12−/− mice into WT C3H (H2k) recipients. Donor mDC (H2-Kb+CD11c+) were quantified in spleens by flow cytometry. Anti-donor T cell reactivity was evaluated by ex vivo carboxyfluorescein diacetate succinimidyl ester-mixed leukocyte reaction and delayed-type hypersensitivity responses, while T effector and regulatory T cells were determined by flow analysis. A threefold to fourfold increase in donor-derived DC was detected in spleens of DAP12−/− liver recipients compared with those given WT grafts. Moreover, pro-inflammatory cytokine gene expression in the graft, interferon gamma (IFNγ) production by graft-infiltrating CD8+ T cells and systemic levels of IFNγ were all elevated significantly in DAP12−/− liver recipients. DAP12−/− grafts also exhibited reduced incidences of CD4+Foxp3+ cells and enhanced CD8+ T cell IFNγ secretion in response to donor antigen challenge. Unlike WT grafts, DAP12−/− livers failed to induce tolerance and were rejected acutely. Thus, DAP12 expression in liver grafts regulates donor mDC migration to host lymphoid tissue, alloreactive T cell responses and transplant tolerance.