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Complement-activated interferon-γ–primed human endothelium transpresents interleukin-15 to CD8+ T cells
Catherine B. Xie, … , Dan Jane-wit, Jordan S. Pober
Catherine B. Xie, … , Dan Jane-wit, Jordan S. Pober
Published March 19, 2020
Citation Information: J Clin Invest. 2020;130(7):3437-3452. https://doi.org/10.1172/JCI135060.
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Research Article Immunology Article has an altmetric score of 48

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

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Abstract

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.

Authors

Catherine B. Xie, Bo Jiang, Lingfeng Qin, George Tellides, Nancy C. Kirkiles-Smith, Dan Jane-wit, Jordan S. Pober

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Figure 5

MCC950 blocks MAC-induced NLRP3 inflammasome activation by human ECs lining human artery xenografts and reduces the enhanced allogeneic memory T cell infiltration in vivo.

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MCC950 blocks MAC-induced NLRP3 inflammasome activation by human ECs lin...
(A) Human coronary artery grafts from a single donor were implanted into a set of 4 SCID/bg immunodeficient mice and quiesced for 7 days before pretreatment with NLRP3 inhibitor MCC950 or control DMSO in PBS before PRA or IgG– sera treatment. After 24 hours, grafts were explanted and retransplanted into a second SCID/bg host with circulating allogeneic PBMCs. Osmotic pumps filled with MCC950 or DMSO in PBS were implanted subcutaneously in the second graft recipient at time of retransplantation. Grafts were recovered after 14 days. The experiment was repeated 3 times with different artery donors. (B) Human ECs lining arterial grafts were identified by Ulex staining and analyzed for cleaved caspase-1 staining by immunofluorescence. Scale bars: 50 μm. (C) Neointimal areas of grafts were assessed between treatment groups following EVG staining. Infiltrating intimal CD3+ T cells were identified and quantified following immunohistochemistry staining (n = 3). Scale bars: 50 μm. Data represent mean ± SEM. *P < 0.05, 1-way ANOVA and Tukey’s multiple comparisons test. Results shown are representative of 3 artery grafts from 3 different artery donors.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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