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Human microvascular endothelium confers peripheral T cell tolerance via secondary inhibitory signals: insight from kidney checkpoint inhibitor toxicity 2857

Year: 2025
Type: article
Abstract: Description Normal human kidney microvascular endothelium expresses high levels of HLA-DR without inflammation despite being exposed to circulating proteins which could be processed to antigens recognized by T cells. Using tissue cytometry and T-cell assays to investigate the role of HLA-DR and secondary inhibitory signals on human kidney microvascular endothelial cells (KMEC) we found: 1) Sensitized T cells are activated when peptide is presented by KMEC of the appropriate HLA-DR specificity. Blockade of CD58 or HLA-DR reduces T cell activation while blockade of CD274 (PD-L1) enhances activation. 2) T cell co-stimulatory and inhibitory molecules on native and transplanted kidneys are identified by flow cytometry. CD274 (PD-L1) expression is high on all KMECs. KMEC also express Inhibitory molecules B7H3 (CD276) and B7H4. 3) Kidneys injured with PD-1/PDL-1 checkpoint inhibitors show an intense perivascular T-lymphocytic infiltrate. 4) Human fetal kidneys express endothelial HLA-DR and CD274 at a similar time in development. These data suggest an endothelium-based mechanism of peripheral tolerance whereby constitutive high expression of CD274 (PDL-1) limits activation of sensitized T cells, even if HLA-DR bound peptide is recognized. This could inhibit autoreactive T cells that escape thymic deletion throughout the lifespan of humans. Findings in the kidney are likely applicable to other human organs which express HLA-DR on their microvascular endothelium. Funding Sources Kidney Immunology Research Fund at the University of Washington Topic Categories Immune Mechanisms of Human Disease (HUM)
DOI: 10.1093/jimmun/vkaf283.728
Language: English
Subfield: Immunology
Open Access status: bronze
OpenAlex ID: W4416449183
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