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Primed CD8 + T‐Cell Responses to Allogeneic Endothelial Cells Are Controlled by Local Complement Activation
Author(s) -
Raedler H.,
Yang M.,
Lalli P. N.,
Medof M. E.,
Heeger P. S.
Publication year - 2009
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2009.02723.x
Subject(s) - c5a receptor , decay accelerating factor , cd8 , complement system , microbiology and biotechnology , t cell , cytotoxic t cell , immunology , complement membrane attack complex , proinflammatory cytokine , medicine , biology , inflammation , immune system , in vitro , biochemistry
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 IFNγ + 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.