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Human Corneal Endothelial Cells Expressing Programmed Death-Ligand 1 (PD-L1) Suppress PD-1⁺ T Helper 1 Cells by a Contact-Dependent Mechanism

¹From the Department of Ophthalmology & Visual Science, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo, Japan; the ²Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan; the ³Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan; the ⁴Department of Ophthalmology, University of Tokyo Graduate School of Medicine, Tokyo, Japan; the ⁵Department of Ophthalmology, Tokyo Women’s Medical University Medical Center East, Tokyo, Japan; and the ⁶Corneal Regeneration Research Team, Foundation for Biomedical Research and Innovation, Kobe, Japan.

PURPOSE. This study was designed to determine whether human corneal endothelial (HCE) cells could regulate the activation of bystander T cells in vitro.

METHODS. HCE cell lines were established from primary HCE cells. Target-activated T cells were used allogeneic T cells and Jurkat T-cell lines. As an additional target, T-cell clones from uveitis patients were established from aqueous humor via a limiting dilution. T-cell activation was assessed for proliferation by [³H]-thymidine incorporation, carboxyfluorescein succinimidyl ester incorporation, or IFN production. Expression of co-stimulatory molecules on IFN-treated corneal endothelial and non-treated cells was evaluated by flow cytometry, RT-PCR, or immunohistochemistry. Expression of co-stimulatory receptors on target T cells was evaluated by flow cytometry. Blocking antibodies was used to abolish the HCE-inhibitory function.

RESULTS. HCE cells suppressed both in vitro proliferation and IFN production by CD4⁺ T cells via a cell contact-dependent mechanism. HCE constitutively expressed co-stimulatory molecules programmed death-ligand 1 (PD-L1) and PD-L2, and their expression was enhanced by IFN. HCE efficiently inhibited the proliferation of Th1 cells that overexpressed PD-1 among various activated T-cell lines and clones established from patients with uveitis or corneal endotheliitis. A neutralizing mAb for PD-L1, but not PD-L2, blocked the suppressive effect of HCE on Th1 cells.

CONCLUSIONS. HCE can impair the effector functions and activation of Th1 infiltrating CD4⁺ T cells via the PD-1/PD-L1 interaction. The data support the hypothesis that corneal endothelium may contribute to maintenance of the privileged immune status of the anterior chamber of the eye by inducing peripheral immune tolerance.

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