Invest Ophthalmol Vis Sci. 2009 Dec 17. [Epub ahead of print]
El Annan J, Goyal S, Zhang Q, Freeman G, Sharpe A, Dana R.
Ophthalmology, Harvard Medical School, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, United States.
Purpose: Given that dry eye disease (DED) is associated with T cell-mediated inflammation of the ocular surface, and PD-L1 is an important 'negative' or inhibitory regulator of immune responses that is constitutively expressed at high levels by corneal epithelial cells, we studied the expression and function of PD-L1 in DED.
Methods: Dry eye was induced in untreated wild-type mice, PD-L1-/- mice, and wild-type mice treated with anti-PD-L1 antibody by exposing these mice to a desiccating environment in the controlled environment chamber (CEC) modified with subcutaneous administration of scopolamine. Real-time PCR was used to quantify the expression of chemokine gene transcript levels of multiple CC and CXC chemokine ligands and receptors. Epifluorescent microscopy was used to evaluate corneal infiltration of CD3+ T cells after immunohistochemical staining.
Results: The increased expression of specific chemokine ligands and receptors in PD-L1-/- corneas of normal mice is associated with significant increase in T cell homing into these corneas. Similar, and more enhanced increases in T cell infiltration were observed in PD-L1-/-DED mice or DED mice treated with anti-PD-L1 antibody as compared to controls. In addition, we found a significantly decreased expression of PD-L1 by corneal epithelial cells in DED and a significantly increased corneal fluorescein staining score with PD-L1 functional blockade using anti-PD-L1 antibody.
Conclusion: Downregulation of corneal epithelial PD-L1 amplifies dry eye-associated corneal inflammation and epitheliopathy by increasing the expression of chemokine ligands and receptors that promote T cell homing to the ocular surface.
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