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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 7

Anti–IL-15 blocking antibody reduces intimal CD8+ T cell infiltration and expression of effector molecules.

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Anti–IL-15 blocking antibody reduces intimal CD8+ T cell infiltration an...
(A) Human coronary artery grafts from the same donor were implanted into sets of 4 immunodeficient mice. Recipients were pretreated with anti–human IL-15 blocking antibody (αIL-15) or control isotype antibody before PRA or control sera treatment. Grafts were retransplanted into a second recipient with circulating allogeneic human PBMCs and similarly treated with anti–IL-15 blocking antibody or isotype control (n = 3). (B) qRT-PCR analysis of IL-15 and IL-15Rα (normalized to CD31); IFN-γ, CD4, CD8 (normalized to GAPDH); and granzyme B and perforin (normalized to CD8) in the grafts. Normalized expression is relative to isotype and IgG– control group (n = 3). (C) Immunofluorescence detection of CD8 or IL-15 expression and human endothelium by Ulex in grafts. The intimal infiltrating CD8+ T cells were quantified. Scale bars: 50 μm. Data represent mean SEM. *P < 0.05; **P < 0.01; 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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