[HTML][HTML] Complement-activated interferon-γ–primed human endothelium transpresents interleukin-15 to CD8+ T cells
CB Xie, B Jiang, L Qin, G Tellides… - The Journal of …, 2020 - Am Soc Clin Investig
The Journal of Clinical Investigation, 2020•Am Soc Clin Investig
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-κB–inducing kinase (NIK)
protein. Endosomal NIK activates both noncanonical NF-κB signaling to synthesize pro–IL-
1β and an NLRP3 inflammasome to process and secrete active IL-1β. IL-1β activates ECs …
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-κB–inducing kinase (NIK)
protein. Endosomal NIK activates both noncanonical NF-κB signaling to synthesize pro–IL-
1β and an NLRP3 inflammasome to process and secrete active IL-1β. IL-1β activates ECs …
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-κB–inducing kinase (NIK) protein. Endosomal NIK activates both noncanonical NF-κB signaling to synthesize pro–IL-1β and an NLRP3 inflammasome to process and secrete active IL-1β. IL-1β activates ECs, increasing recruitment and activation of alloreactive effector memory CD4+ T (Tem) cells. Here, we report that IFN-γ priming induced nuclear expression of IL-15/IL-15Rα complexes in cultured human ECs and that MAC-induced IL-1β stimulated translocation of IL-15/IL-15Rα complexes to the EC surface in a canonical NF-κB–dependent process in which IL-15/IL-15Rα 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-15Rα 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.
The Journal of Clinical Investigation