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Immature and Mature CD8⁺ Dendritic Cells Prolong the Survival of Vascularized Heart Allografts¹

Peta J. O’Connell^2,*,, Wei Li^3,*,, Zhiliang Wang^*,, Susan M. Specht^*,, Alison J. Logar^*, and Angus W. Thomson^*,,

^* Thomas E. Starzl Transplantation Institute and Departments of Surgery and Molecular Genetics and Biochemistry, University of Pittsburgh Medical Center, Pittsburgh, PA 15213

CD8⁺ and CD8^- dendritic cells (DCs) arise from committed bone marrow progenitors and can induce or regulate immune reactivity. Previously, the maturational status of CD8^- (myeloid) DCs has been shown to influence allogeneic T cell responses and allograft survival. Although CD8⁺ 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 CD8^- counterparts, mature CD8⁺ 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 CD8⁺ and CD8^- DCs administered under the same experimental conditions significantly prolonged transplant survival. These observations demonstrate for the first time the innate capacity of CD8⁺ 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.