Abstract: FR-PO272
The Conundrum of Normal Kidney Endothelial HLA-DR Clarified by Checkpoint Inhibitor Toxicity: A Role for Microvascular Endothelium in Peripheral Tolerance
Session Information
- Onconephrology: From AKI to CKD and Everything in Between
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Onconephrology
- 1700 Onconephrology
Author
- Muczynski, Kimberly A., University of Washington, Seattle, Washington, United States
Background
Years ago we reported high constitutive expression of HLA-DR on microvascular endothelial cells of normal human kidney in the absence of inflammation. This surprised us and seemed incongruent with what is known about HLA class II antigen processing. Peptides bound to class II molecules are derived from the uptake of extracellular proteins which get processed intracellularly and then exported to the cell surface bound to HLA-DR where they can be recognized by specific T cell receptors. Would it, therefore, not be dangerous to have kidney endothelial cells constitutively express HLA-DR on their surface where they might encounter and activate circulating T cells?
Methods
We used flow cytometry and and T cell activity assays to investigate the role of HLA-DR on human kidney microvascular endothelial cells (KMEC).
Results
First, we show T cell proliferation and gamma interferon secretion of sensitized T cell when influenza hemagglutinin 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. Second, T cell co-stimulatory and inhibitory molecules on normal native and transplanted kidneys are identified by flow cytometry. CD274 expression is high on all KMECs and T cells within the kidney express CD279 (PD-1). Third, biopsies of acute kidney injury associated with checkpoint inhibitors that block the PD-1, PDL-1 axis show an intense perivascular lymphocytic infiltrate. Finally, human fetal kidneys express endothelial HLA-DR and CD274 at a similar time in development suggesting a fundamental property of the endothelial cells rather than resulting from an immune response.
Conclusion
Taken together, we propose a mechanism of peripheral tolerance whereby KMEC HLA-DR limits activation of sensitized T cells, even if a bound peptide is recognized, because of the constitutive high-co-expression of CD274 (PDL-1).
Funding
- Private Foundation Support