Primed CD8(+) T-cell responses to allogeneic endothelial cells are controlled by local complement activation.
CD8 T cells primed by transplantation recognize allogeneic class I MHC molecules expressed on graft vascular endothelium and contribute to allograft injury. We previously showed that immune cell-derived complement activation fragments are integral to T cell activation/expansion. Herein we tested the impact of local complement production/activation on T cell/endothelial cell (EC) interactions. We found that proinflammatory cytokines upregulated alternative pathway complement production by ECs, yielding C5a. We further found that ECs deficient in the cell surface C3/C5 convertase regulator decay accelerating factor (DAF, CD55) induced greater CD8 T-cell proliferation and more IFNgamma(+) and perforin(+) effector cells than wild-type (WT) ECs. Allogeneic C3(-/-) EC induced little or no CD8 responses. Abrogation of responses following C5a receptor (C5aR) blockade, or augmentation following addition of recombinant C5a demonstrated that the effects were mediated through T-cell-expressed-C5aR interactions. Analyses of in vivo CD8 cell responses to transplanted heart grafts deficient in EC DAF showed similar augmentation. The findings reveal that EC-derived complement triggers secondary CD8 T-cell differentiation and expansion and argue that targeting complement and/or C5aR could limit T-cell-mediated graft injury.
Raedler
H
H
Department of Medicine, Recanati Transplant Institute, Mount Sinai School of Medicine, New York, NY, USA.
Yang
M
M
Lalli
P N
PN
Medof
M E
ME
Heeger
P S
PS
D000818:Animals; D018958:CD55 Antigens / Q000235:genetics / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002450:Cell Communication / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism; D050577:Complement C3-C5 Convertases / Q000235:genetics / Q000378:metabolism; D015936:Complement C5a / Q000235:genetics / Q000378:metabolism; D003165:Complement System Proteins / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000378:metabolism
D018958:CD55 Antigens; D003176:Complement C3; D016207:Cytokines; D044087:Receptor, Anaphylatoxin C5a; C521184:decay-accelerating factor 1, mouse; D015936:Complement C5a; D003165:Complement System Proteins; D050577:Complement C3-C5 Convertases