title: Donor deficiency of decay-accelerating factor accelerates murine T cell-mediated cardiac allograft rejection.
abstract: 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.
authors.affiliation: Department of Medicine, Transplant Institute and Immunology Institute, Mount. Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Vasile
authors.initials: V
authors.lastname: Pavlov
authors.forename: Hugo
authors.initials: H
authors.lastname: Raedler
authors.forename: Shuguang
authors.initials: S
authors.lastname: Yuan
authors.forename: Staci
authors.initials: S
authors.lastname: Leisman
authors.forename: Wing-Hong
authors.initials: WH
authors.lastname: Kwan
authors.forename: Peter N
authors.initials: PN
authors.lastname: Lalli
authors.forename: M Edward
authors.initials: ME
authors.lastname: Medof
authors.forename: Peter S
authors.initials: PS
authors.lastname: Heeger
mesh_terms: D000818:Animals; D018958:CD55 Antigens / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003167:Complement Activation / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D010865:Pilot Projects; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D018958:CD55 Antigens; C521184:decay-accelerating factor 1, mouse
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