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.