DAP12 deficiency in liver allografts results in enhanced donor DC migration, augmented effector T cell responses and abrogation of transplant tolerance (TRAN3P.883)

Abstract

Abstract 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 12kDa (DAP12) negatively regulated conventional liver DC maturation and their in vivo migratory and T cell allostimulatory ability. Livers were transplanted from B6 wild-type (wt) or DAP12-/- mice into wt C3H recipients. Donor DC (H2-Kb+CD11c+) were quantified in spleens by flow cytometry. Anti-donor T cell reactivity was evaluated by ex vivo CFSE-MLR and in vivo delayed-type hypersensitivity responses, while T effector and regulatory T cells were determined by flow analysis. A 3-4-fold increase in donor-derived DC was detected in the spleens of DAP12-/- liver recipients compared with those given wt grafts. Moreover, pro-inflammatory cytokine gene expression in the graft, IFNγ production by graft-infiltrating CD8+ T cells, and systemic levels of IFNγ were all elevated significantly in hosts of 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 DC migration to host lymphoid tissue, alloreactive T cell responses and transplant tolerance.