Th156 - Secondary Inhibitory Signals on Human Kidney Microvascular Endothelium Confer Peripheral T Cell Tolerance: Insight from Checkpoint Inhibitor Toxicity

Abstract Text: The microvascular endothelium of normal human kidney expresses high levels of HLA-DR without inflammation. This surprised us given what is known of HLA class II antigen processing. Would it not be dangerous to have HLA-DR exposed to circulating protein debris that could be endocytosed and 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 and T cells within the kidney express CD279 (PD-1). Inhibitory molecules B7H3 (CD276) and B7H4 are also expressed on KMEC.
3) Biopsies of 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.
Taken together, we propose 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.