Laboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Laboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Exp Eye Res. 2024 Sep;246:110006. doi: 10.1016/j.exer.2024.110006. Epub 2024 Jul 14.
Regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis, and their dysfunction is implicated in the pathogenesis of various autoimmune disorders, including dry eye disease (DED). Treg dysfunction in DED allows T-helper cell 17 (Th17) mediated chronic inflammation at the ocular surface. In this study, the factors causing Treg dysfunction in DED were investigated. We observed reduced expression of Treg functional markers - FoxP3, CD25, and CTLA-4 in the cells isolated from DED mice (DED Tregs). Additionally, DED Tregs showed increased expression levels of receptors for pro-inflammatory cytokine receptors, namely IL-6R, IL-17RA, and IL-23R. An increased expression level of pro-inflammatory cytokine receptors was observed on exposing Tregs isolated from naïve mice (NTregs) to IL-6 or IL-17, but not IL-23, with a concomitant downregulation of FoxP3, CD25, and CTLA-4 in these cells. Furthermore, among these cytokines, IL-6 induced the most pronounced loss of Treg mediated suppression of Th17 proliferation and IL-10 secretion. In vitro and in vivo blockade of IL-6 effectively restored function in DED Tregs, leading to enhanced suppressive function against proliferating Th17 cells and ameliorating disease severity. In conclusion, this study provides insights into mechanisms of Treg dysregulation in DED, specifically delineating the effect of Th17-associated cytokines, with IL-6 emerging as the critical factor inducing Treg dysfunctionality. These findings highlight the potential for developing novel therapeutic interventions for DED through restoration of immunosuppressive function of Tregs.
调节性 T 细胞（Tregs）在维持免疫稳态中发挥着关键作用，其功能障碍与各种自身免疫性疾病的发病机制有关，包括干燥性眼病（DED）。DED 中的 Treg 功能障碍允许 T 辅助细胞 17（Th17）介导眼表面的慢性炎症。在这项研究中，研究了导致 DED 中 Treg 功能障碍的因素。我们观察到从 DED 小鼠中分离的 Treg（DED Treg）中 Treg 功能标志物 FoxP3、CD25 和 CTLA-4 的表达减少。此外，DED Treg 表现出促炎细胞因子受体（即 IL-6R、IL-17RA 和 IL-23R）的表达水平增加。将来自幼稚小鼠（NTregs）的 Treg 暴露于 IL-6 或 IL-17 时，观察到促炎细胞因子受体的表达水平增加，但暴露于 IL-23 时则不然，同时这些细胞中的 FoxP3、CD25 和 CTLA-4 下调。此外，在这些细胞因子中，IL-6 诱导 Treg 介导的 Th17 增殖和 IL-10 分泌抑制作用的丧失最为明显。体内外阻断 IL-6 可有效恢复 DED Treg 的功能，增强对增殖性 Th17 细胞的抑制作用，并改善疾病严重程度。总之，这项研究深入了解了 DED 中 Treg 失调的机制，特别说明了 Th17 相关细胞因子的作用，其中 IL-6 是诱导 Treg 功能障碍的关键因素。这些发现强调了通过恢复 Treg 的免疫抑制功能为 DED 开发新型治疗干预措施的潜力。
