Alloantibodies in pre-sensitized transplant candidates deposit complement membrane attack complexes (MAC) on graft endothelial cells (ECs), increasing risk of CD8+ T cell-mediated acute rejection. We recently showed (a) human ECs endocytose MAC into Rab5+ endosomes, creating a signaling platform that stabilizes NF-κB–inducing kinase (NIK) protein; (b) endosomal NIK activates both non-canonical NF-κB signaling to synthesize pro-IL-1β and an NLRP3 inflammasome to process and secrete active IL-1β; and (c) IL-1β activates ECs, increasing recruitment and activation of alloreactive effector memory CD4+ T (TEM) cells. Here, we report 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, where IL-15/IL-15Rα transpresentation increased activation and maturation of alloreactive CD8+ TEM. Blocking NLRP3 inflammasome assembly, IL-1 receptor or IL-15 on ECs inhibited the augmented CD8+ TEM responses, indicating this pathway was 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.
Catherine B. Xie, Bo Jiang, Lingfeng Qin, George Tellides, Nancy C. Kirkiles-Smith, Dan Jane-wit, Jordan S. Pober
Usage data is cumulative from March 2020 through March 2020.
Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.
Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.