title: Immature and mature CD8alpha+ dendritic cells prolong the survival of vascularized heart allografts.
abstract: CD8alpha+ and CD8alpha- dendritic cells (DCs) arise from committed bone marrow progenitors and can induce or regulate immune reactivity. Previously, the maturational status of CD8alpha-(myeloid) DCs has been shown to influence allogeneic T cell responses and allograft survival. Although CD8alpha+ DCs have been implicated in central tolerance and found to modulate peripheral T cell function, their influence on the outcome of organ transplantation has not been examined. Consistent with their equivalent high surface expression of MHC and costimulatory molecules, sorted mature C57BL/10J (B10; H2(b)) DCs of either subset primed naive, allogeneic C3H/HeJ (C3H; H2(k)) recipients for Th1 responses. Paradoxically and in contrast to their CD8alpha- counterparts, mature CD8alpha+ B10 DCs given systemically 7 days before transplant markedly prolonged B10 heart graft survival in C3H recipients. This effect was associated with specific impairment of ex vivo antidonor T cell proliferative responses, which was not reversed by exogenous IL-2. Further analyses of possible underlying mechanisms indicated that neither immune deviation nor induction of regulatory cells was a significant contributory factor. In contrast to the differential capacity of the mature DC subsets to affect graft outcome, immature CD8alpha+ and CD8alpha- DCs administered under the same experimental conditions significantly prolonged transplant survival. These observations demonstrate for the first time the innate capacity of CD8alpha+ DCs to regulate alloimmune reactivity and transplant survival, independent of their maturation status. Mobilization of such a donor DC subset with capacity to modulate antidonor immunity may have significant implications for the therapy of allograft rejection.
authors.affiliation: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. peta@rri.ca
authors.forename: Peta J
authors.initials: PJ
authors.lastname: O'Connell
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Wang
authors.forename: Susan M
authors.initials: SM
authors.lastname: Specht
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Logar
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016827:CD8 Antigens / Q000032:analysis*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D006084:Graft Rejection / Q000276:immunology* / Q000628:therapy; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D016130:Immunophenotyping; D007519:Isoantigens / Q000276:immunology; D007700:Kinetics; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018417:Th1 Cells / Q000276:immunology
chemical_list: D016827:CD8 Antigens; C431698:CD8alpha antigen; D016207:Cytokines; D007519:Isoantigens