Singh Rohan B, Blanco Tomas, Mittal Sharad K, Alemi Hamid, Chauhan Sunil K, Chen Yihe, Dana Reza
Laboratory of Corneal Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
Laboratory of Corneal Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
Am J Pathol. 2021 Apr;191(4):720-729. doi: 10.1016/j.ajpath.2021.01.003. Epub 2021 Jan 14.
Pigment epithelium-derived factor (PEDF) is a widely expressed 50-kDa glycoprotein belonging to the serine protease inhibitor family, with well-established anti-inflammatory functions. Recently, we demonstrated the immunoregulatory role played by PEDF in dry eye disease (DED) by suppressing the maturation of antigen-presenting cells at the ocular surface following exposure to the desiccating stress. In this study, we evaluated the effect of PEDF on the immunosuppressive characteristics of regulatory T cells (Tregs), which are functionally impaired in DED. In the presence of PEDF, the in vitro cultures prevented proinflammatory cytokine (associated with type 17 helper T cells)-induced loss of frequency and suppressive phenotype of Tregs derived from normal mice. Similarly, PEDF maintained the in vitro frequency and enhanced the suppressive phenotype of Tregs derived from DED mice. On systemically treating DED mice with PEDF, moderately higher frequencies and significantly enhanced suppressive function of Tregs were observed in the draining lymphoid tissues, leading to the efficacious amelioration of the disease. Our results demonstrate that PEDF promotes the suppressive capability of Tregs and attenuates their type 17 helper T-cell-mediated dysfunction in DED, thereby playing a role in the suppression of DED.
色素上皮衍生因子（PEDF）是一种广泛表达的50 kDa糖蛋白，属于丝氨酸蛋白酶抑制剂家族，具有公认的抗炎功能。最近，我们通过抑制暴露于干燥应激后眼表抗原呈递细胞的成熟，证明了PEDF在干眼病（DED）中发挥的免疫调节作用。在本研究中，我们评估了PEDF对调节性T细胞（Tregs）免疫抑制特性的影响，调节性T细胞在DED中功能受损。在存在PEDF的情况下，体外培养可防止促炎细胞因子（与17型辅助性T细胞相关）诱导的正常小鼠来源的Tregs频率和抑制表型丧失。同样，PEDF维持了DED小鼠来源的Tregs的体外频率，并增强了其抑制表型。在用PEDF全身治疗DED小鼠后，在引流淋巴组织中观察到Tregs频率适度升高且抑制功能显著增强，从而有效改善了疾病。我们的结果表明，PEDF促进了Tregs的抑制能力，并减轻了它们在DED中17型辅助性T细胞介导的功能障碍，从而在抑制DED中发挥作用。
