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* Department of Medicine, Transplant Institute and Immunology Institute, Mount. Sinai School of Medicine, New York, NY 10029;
Department of Immunology, Cleveland Clinic, Cleveland, OH 44195; and
Institute of Pathology, Case Western Reserve University, Cleveland OH 44106
Decay-accelerating factor (DAF) is a cell surface regulator that accelerates the dissociation of C3/C5 convertases and thereby prevents the amplification of complement activation on self cells. In the context of transplantation, DAF has been thought to primarily regulate antibody-mediated allograft injury, which is in part serum complement-dependent. Based on our previously delineated link between DAF and CD4 T cell responses, we evaluated the effects of donor Daf1 (the murine homolog of human DAF) deficiency on CD8 T cell-mediated cardiac allograft rejection. MHC-disparate Daf1–/– allografts were rejected with accelerated kinetics compared with wild-type grafts. The accelerated rejection predominantly tracked with DAF’s absence on bone marrow-derived cells in the graft and required allograft production of C3. Transplantation of Daf1–/– hearts into wild-type allogeneic hosts augmented the strength of the anti-donor (direct pathway) T cell response, in part through complement-dependent proliferative and pro-survival effects on alloreactive CD8 T cells. The accelerated allograft rejection of Daf1–/– hearts occurred in recipients lacking anti-donor Abs. The results reveal that donor DAF expression, by controlling local complement activation on interacting T cell APC partners, regulates the strength of the direct alloreactive CD8+ T cell response. The findings provide new insights into links between innate and adaptive immunity that could be exploited to limit T cell-mediated injury to an allograft following transplantation.
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1 This work was supported by the Roche Organ Transplant Research Fund (P.S.H.) and by National Institutes of Health Grants AI43578 (P.S.H.) and AI23598 (M.E.M.). P.N.L. received a fellowship grant from the Ohio Affiliate of the American Heart Association.
2 V.P. and H.R. contributed equally to this paper.
3 Address correspondence and reprint requests to Dr. Peter S. Heeger, Mount Sinai School of Medicine, Box 1243, One Gustave L. Levy Plaza, New York, NY 10029. E-mail address: peter.heeger{at}mssm.edu
4 Abbreviations used in this paper: DAF, decay-accelerating factor; BM, bone marrow; MST, median survival time; WT, wild type.
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