title: DAP12 deficiency in liver allografts results in enhanced donor DC migration, augmented effector T cell responses and abrogation of transplant tolerance.
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 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(H2(b) ) (B6) WT or DAP12(-/-) mice into WT C3H (H2(k) ) recipients. Donor mDC (H2-K(b+) 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.
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: O
authors.initials: O
authors.lastname: Yoshida
authors.forename: S
authors.initials: S
authors.lastname: Kimura
authors.forename: L
authors.initials: L
authors.lastname: Dou
authors.forename: B M
authors.initials: BM
authors.lastname: Matta
authors.forename: S
authors.initials: S
authors.lastname: Yokota
authors.forename: M A
authors.initials: MA
authors.lastname: Ross
authors.forename: D A
authors.initials: DA
authors.lastname: Geller
authors.forename: A W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D002465:Cell Movement; D017690:Cell Transplantation; D003713:Dendritic Cells / Q000166:cytology*; D007249:Inflammation; D007962:Leukocytes / Q000166:cytology; D008099:Liver / Q000378:metabolism; D016031:Liver Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C484963:Tyrobp protein, mouse
keywords: DAP12; T cells; dendritic cells; liver transplant; tolerance