DAP12 Deficiency in Liver Allografts Results in Enhanced Donor DC Migration, Augmented Effector T Cell Responses and Abrogation of Transplant 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. The authors' data suggest that expression of the transmembrane immunoadaptor DNAX‐activating protein of 12 kDa in mouse liver allografts regulates donor dendritic cell migration to host lymphoid tissue, down‐modulates effector T cell responses, and promotes transplant tolerance.