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Dendritic cells (DC) are specialized antigen-presenting cells for the induction of cell-mediated immunity, including graft rejection.1 Evidence also exists, however, for their tolerogenicity.2,3 We have previously shown that GM-CSF-stimulated mouse bone marrow (BM)-derived DC progenitors that express cell surface MHC class II antigens but are deficient in expression of the costimulatory molecules B7-1 (CD80) and B7-2 (CD86) can induce alloantigen-specific T cell anergy in vitro.4 In the present study, we tested the in vivo relevance of these findings in a vascularized cardiac allograft model.
C57BL/10 (B10; H2b), C3H (H2k), or BALB/c (H2d) mouse BM-derived DC progenitors, propagated in GM-CSF as described previously,5 were injected intravenously into normal C3H (H2k) recipients. Seven days later, the mice received abdominal heart transplants from normal B10 donors.6 No immunosuppressive treatment was given. Spleen T cells from the C3H mice seven days after the injection of DC progenitors of B10 donors were used as responder/effector cells in mixed leukocyte reaction (MLR) and cytotoxic T lymphocyte (CTL) assays. Cell surface phenotype was analyzed by flow cytometry with a panel of monoclonal antibodies.
As we reported previously, B10 mouse BM-derived DC progenitors (DEC205+, MHC class II+, B7-1dim, B7-2−) induced allogeneic-specific T cell hyporesponsiveness in C3H T cells in vitro.4 In addition, however, we found that B10 heart grafts were prolonged significantly in C3H mice that were injected intravenously with 2 × 106 of these B10 DC progenitors 7 days before transplantation [median survival time (MST) 22 days vs 9.5 days in control group]. MST was also prolonged although to a lesser extent (16.5 days) in mice that received third-party (BALB/c; H2d) DC progenitors cultured under the same conditions and expressing the same phenotype. However, C3H recipients injected with “mature” GM-CSF + IL-4 stimulated B10 DC (DEC205+, MHC class IIbright, B7-1+, B7-2bright) 7 days before transplant rejected B10 heart grafts in an accelerated fashion (MST 7 days). T cells from C3H mice given B10 B7-2− DC progenitors seven days earlier showed very low MLR responses to donor stimulators, but those from C3H mice injected with B7-2bright B10 DC showed marked proliferative responses to donor stimulators. T cells from C3H mice injected with B10 B7-2− DC progenitors generated lower CTL activity than animals given B7-2bright B10 DC. Amongst the injected donor MHC class II+ DC progenitors that migrated to recipient secondary lymphoid tissue were cells that appeared to have unregulated cell surface B7-1 and B7-2 molecule expression. This observation may at least in part explain the temporary or unstable nature of the hyporesponsiveness induced by donor-derived DC progenitors in non-immunosuppressed recipients.
Supported by NIH grants DK 29961-14 and DK 49745-01A1.