Primed CD8(+) T-cell responses to allogeneic endothelial cells are controlled by local complement activation.

Area of Science:

• Immunology
• Transplantation immunology
• Complement system

Background:

• CD8 T cells recognize allogeneic MHC molecules on graft endothelium, contributing to rejection.
• Immune cell-derived complement activation fragments are crucial for T cell activation and expansion.

Purpose of the Study:

• To investigate the impact of local complement production and activation on T cell-endothelial cell interactions.
• To determine the role of endothelial cell (EC)-derived complement in CD8 T cell responses during allograft rejection.

Main Methods:

• Proinflammatory cytokines were used to upregulate alternative pathway complement production by ECs.
• ECs deficient in decay accelerating factor (DAF, CD55) were compared to wild-type (WT) ECs for their effects on CD8 T cell proliferation and effector function.
• C5a receptor (C5aR) blockade and recombinant C5a addition were used to elucidate the role of C5aR signaling.
• In vivo studies analyzed CD8 cell responses to transplanted heart grafts deficient in EC DAF.

Main Results:

• Proinflammatory cytokines induced ECs to produce C5a via the alternative complement pathway.
• ECs lacking DAF promoted greater CD8 T cell proliferation and increased IFN-gamma(+) and perforin(+) effector cells compared to WT ECs.
• C5aR blockade abrogated responses, while C5a addition augmented them, confirming T cell-expressed C5aR mediation.
• In vivo findings mirrored in vitro results, showing augmented CD8 responses in grafts with EC DAF deficiency.

Conclusions:

• Endothelial cell-derived complement, particularly C5a, significantly drives secondary CD8 T cell differentiation and expansion.
• Targeting the complement system or C5aR on T cells represents a potential therapeutic strategy to mitigate T cell-mediated allograft injury.