CD8+ T cells mediate aortic allograft vasculopathy by direct killing and an interferon-gamma-dependent indirect pathway.
OBJECTIVE
Allograft vasculopathy (AV) has emerged as the major obstacle to long-term survival in clinical heart transplantation. Immune events are implicated in the development of AV, but the cellular and molecular mechanisms involved remain unclear. We sought to determine whether and by what mechanism CD8(+) T lymphocytes are able to generate AV in a murine aortic allograft model.


METHODS
Allo-primed CD8(+) T lymphocytes were transferred into immunodeficient (RAG-1(-/-)) mouse recipients of aortic allografts. We also transferred primed CD8(+) T cells with targeted deletions of effector molecules (perforin, Fas-ligand) to determine the role of direct cytolysis (CTL) in CD8(+) T-cell-mediated AV. We determined the role of non-CTL effector mechanisms through the transfer of either wildtype or interferon-gamma (IFN-gamma)-deficient CD8(+) T cells into RAG-1(-/-) recipients of MHC class I-deficient allografts.


RESULTS
Adoptive transfer of primed wildtype CD8(+) T lymphocytes into immunodeficient recipients of aortic allografts resulted in the development of robust AV lesions. Transfer of CD8(+) T lymphocytes with targeted deletions in CTL effector molecules resulted in reduction of AV lesion size but not abrogation. Transfer of wildtype CD8(+) T cells into recipients of MHC class I-deficient grafts resulted in a reduction in AV lesion size, while transfer of interferon-gamma-deficient CD8(+) T cells into MHC class I-deficient grafts abrogated AV.


CONCLUSIONS
These data indicate that CD8(+) T cells mediate AV through direct cytolysis and a distinct interferon-gamma-dependent non-CTL effector pathway. Given the resistance of this cell type to conventional immunosuppression, these results may have important therapeutic implications.
Skaro
Anton I
AI
Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7.
Liwski
Robert S
RS
Zhou
Juan
J
Vessie
Ellen L
EL
Lee
Timothy D G
TD
Hirsch
Gregory M
GM
D019264:Adoptive Transfer; D000818:Animals; D001012:Aorta, Abdominal / Q000637:transplantation*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D016923:Cell Death; D016572:Cyclosporine / Q000494:pharmacology; D003601:Cytotoxicity Tests, Immunologic; D053222:Fas Ligand Protein; D017353:Gene Deletion; D007114:Immunization; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D009389:Neovascularization, Pathologic; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D014181:Transplantation Immunology; D014184:Transplantation, Homologous
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D007371:Interferon-gamma; D016572:Cyclosporine