Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
Graduate Program in Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
J Immunol. 2018 Jun 1;200(11):3711-3719. doi: 10.4049/jimmunol.1700417. Epub 2018 Apr 18.
Immune privilege helps protect the cornea from damaging inflammation but can also impair pathogen clearance from this mucosal surface. Programmed death-ligand 1 (PD-L1 or B7-H1) contributes to corneal immune privilege by inhibiting the function of a variety of immune cells. We asked whether programmed death-1 (PD-1)/PD-L1 interaction regulates HSV-1 clearance from infected corneas. We show that PD-L1 is constitutively expressed in the corneal epithelium and is upregulated upon HSV-1 corneal infection, with peak expression on CD45 cells NK cells, dendritic cells, neutrophils, and macrophages and CD45 corneal epithelial cells at 4 d postinfection (dpi). As early as 1 dpi, HSV-1-infected corneas of B7-H1 mice as compared with wild-type mice showed increased chemokine expression and this correlated with increased migration of inflammatory cells into the viral lesions and decreased HSV-1 corneal titers. Local PD-L1 blockade caused a similar increase in viral clearance, suggesting a local effect of PD-1/PD-L1 in the cornea. The enhanced HSV-1 clearance at 2 dpi resulting from PD-1/PD-L1 blockade is mediated primarily by a monocyte/macrophage population. Studies in bone marrow chimeras demonstrated enhanced viral clearance when PD-L1 was absent only from nonhematopoietic cells. We conclude that PD-L1 expression on corneal cells negatively impacts the ability of the innate immune system to clear HSV-1 from infected corneas.
免疫特权有助于保护角膜免受炎症损伤，但也会损害从这些黏膜表面清除病原体的能力。程序性死亡配体 1（PD-L1 或 B7-H1）通过抑制各种免疫细胞的功能来促进角膜免疫特权。我们想知道程序性死亡受体 1（PD-1）/PD-L1 相互作用是否调节单纯疱疹病毒 1（HSV-1）从受感染角膜的清除。我们发现 PD-L1 在角膜上皮细胞中持续表达，并在 HSV-1 角膜感染时上调，在感染后 4 天（dpi），CD45 细胞（NK 细胞、树突状细胞、中性粒细胞和巨噬细胞）和 CD45 角膜上皮细胞上表达最高。早在 1 dpi，与野生型小鼠相比，B7-H1 小鼠的 HSV-1 感染角膜表现出趋化因子表达增加，这与炎症细胞向病毒病变部位的迁移增加和 HSV-1 角膜滴度降低相关。局部 PD-L1 阻断导致病毒清除率相似增加，表明 PD-1/PD-L1 在角膜中有局部作用。由于 PD-1/PD-L1 阻断，在 2 dpi 时导致 HSV-1 清除增强主要是通过单核细胞/巨噬细胞群介导的。骨髓嵌合体研究表明，当 PD-L1 仅不存在于非造血细胞中时，病毒清除增强。我们得出结论，角膜细胞上的 PD-L1 表达会对先天免疫系统清除感染角膜中的 HSV-1 的能力产生负面影响。
