Complement-activated interferon-γ-primed human endothelium transpresents interleukin-15 to CD8+ T cells

Area of Science:

• Immunology
• Transplantation Biology
• Cellular Signaling

Background:

• Alloantibodies and complement membrane attack complexes (MACs) increase acute rejection risk.
• Endothelial cells (ECs) internalize MACs, activating NF-κB-inducing kinase (NIK) and inflammasomes.
• This leads to IL-1β secretion, activating CD4+ T cells.

Purpose of the Study:

• To investigate the role of IL-15/IL-15Rα in alloantibody-mediated CD8+ T cell activation.
• To elucidate the signaling pathway linking MACs to CD8+ T cell responses in transplantation.

Main Methods:

• Cultured human ECs treated with IFN-γ and MACs.
• Analysis of IL-15/IL-15Rα expression and translocation.
• Blocking experiments targeting NLRP3 inflammasome, IL-1 receptor, and IL-15.
• In vivo studies using human coronary artery grafts in immunodeficient mice.

Main Results:

• IFN-γ induced nuclear IL-15/IL-15Rα in ECs.
• MAC-induced IL-1β promoted IL-15/IL-15Rα surface translocation via NF-κB.
• IL-15/IL-15Rα transpresentation augmented CD8+ T cell activation.
• Inhibition of inflammasomes or IL-15 blocked these responses.
• In vivo, alloantibody induced IL-15/IL-15Rα expression and CD8+ T cell infiltration, reduced by inflammasome inhibition.

Conclusions:

• MAC-induced IL-1β activates a pathway involving EC IL-15/IL-15Rα transpresentation that enhances CD8+ T cell responses.
• This pathway links alloantibody deposition to CD8+ T cell-mediated acute rejection.
• Targeting MAC signaling, inflammasomes, or IL-15 may prevent transplant rejection.