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

Alloantibodies in presensitized transplant candidates deposit complement membrane attack complexes (MACs) on graft endothelial cells (ECs), increasing risk of CD8(+) T cell-mediated acute rejection. We recently showed that human ECs endocytose MACs into Rab5(+) endosomes, creating a signaling platform that stabilizes NF-kappa B-inducing kinase (NIK) protein. Endosomal NIK activates both noncanonical NF-kappa B signaling to synthesize pro-IL-1 beta and an NLRP3 inflammasome to process and secrete active IL-1 beta. IL-1 beta activates ECs, increasing recruitment and activation of alloreactive effector memory CD4(+) T (Tem) cells. Here, we report that IFN-gamma priming induced nuclear expression of IL-15/IL-15R alpha complexes in cultured human ECs and that MAC-induced IL-1 beta stimulated translocation of IL-15/IL-15R alpha complexes to the EC surface in a canonical NF-kappa B-dependent process in which IL-15/IL-15R alpha transpresentation increased activation and maturation of alloreactive CD8(+) Tem cells. Blocking NLRP3 inflammasome assembly, IL-1 receptor, or IL-15 on ECs inhibited the augmented CD8(+) Tem cell responses, indicating that this pathway is not redundant. Adoptively transferred alloantibody and mouse complement deposition induced IL-15/IL-15R alpha expression by human ECs lining human coronary artery grafts in immunodeficient mice, and enhanced intimal CD8(+) T cell infiltration, which was markedly reduced by inflammasome inhibition, linking alloantibody to acute rejection. Inhibiting MAC signaling may similarly limit other complement-mediated pathologies.