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

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-?B-inducing kinase (NIK) protein. Endosomal NIK activates both noncanonical NF-?B signaling to synthesize pro-IL-1? and an NLRP3 inflammasome to process and secrete active IL-1?. IL-1? activates ECs, increasing recruitment and activation of alloreactive effector memory CD4+ T (Tem) cells. Here, we report that IFN-? priming induced nuclear expression of IL-15/IL-15R? complexes in cultured human ECs and that MAC-induced IL-1? stimulated translocation of IL-15/IL-15R? complexes to the EC surface in a canonical NF-?B-dependent process in which IL-15/IL-15R? 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? 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.

SUBMITTER: Xie CB

PROVIDER: S-EPMC7324183 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Xie Catherine B CB Jiang Bo B Qin Lingfeng L Tellides George G Kirkiles-Smith Nancy C NC Jane-Wit Dan D Pober Jordan S JS

The Journal of clinical investigation 20200701 7

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- ...[more]

PMID: 32191642

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Project description:RationaleComplement activation contributes to multiple immune-mediated pathologies. In late allograft failure, donor-specific antibody deposits complement membrane attack complexes (MAC) on graft endothelial cells (ECs), substantially increasing their immunogenicity without causing lysis. Internalized MAC stabilize NIK (NF-κB [nuclear factor kappa-light-chain-enhancer of activated B cells]-inducing kinase) protein on Rab5+MAC+ endosomes, activating noncanonical NF-κB signaling. However, the link to increased immunogenicity is unclear.ObjectiveTo identify mechanisms by which alloantibody and internalized MAC activate ECs to enhance their ability to increase T-cell responses.Methods and resultsIn human EC cultures, internalized MAC also causes NLRP3 (NOD-like receptor family pyrin domain containing 3) translocation from endoplasmic reticulum to Rab5+MAC+NIK+ endosomes followed by endosomal NIK-dependent inflammasome assembly. Cytosolic NIK, stabilized by LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells), does not trigger inflammasome assembly, and ATP-triggered inflammasome assembly does not require NIK. IFN-γ (interferon-γ) primes EC responsiveness to MAC by increasing NLRP3, pro-caspase 1, and gasdermin D expression. NIK-activated noncanonical NF-κB signaling induces pro-IL (interleukin)-1β expression. Inflammasome processed pro-IL-1β, and gasdermin D results in IL-1β secretion that increases EC immunogenicity through IL-1 receptor signaling. Activation of human ECs lining human coronary artery grafts in immunodeficient mouse hosts by alloantibody and complement similarly depends on assembly of an NLRP3 inflammasome. Finally, in renal allograft biopsies showing chronic rejection, caspase-1 is activated in C4d+ ECs of interstitial microvessels, supporting the relevance of the cell culture findings.ConclusionsIn response to antibody-mediated complement activation, IFN-γ-primed human ECs internalize MAC, triggering both endosomal-associated NIK-dependent NLRP3 inflammasome assembly and IL-1 synthesis, resulting in autocrine/paracrine IL-1β-mediated increases in EC immunogenicity. Similar responses may underlie other complement-mediated pathologies.

Dataset Information

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

Publications

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

Similar Datasets

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