Department of Ophthalmology and Vision Sciences, University of Louisville, 301 E. Muhammad Ali Blvd., Louisville, KY 40202, USA.
J Leukoc Biol. 2010 Dec;88(6):1241-9. doi: 10.1189/jlb.0610332. Epub 2010 Aug 25.
We previously reported that after exposure to inflammatory cytokines, such as IL-17 and IFN-γ, RPE cells express increased amounts of suppressor of cytokine signaling, leading to general suppression of the inflammatory response. Here, we demonstrate that RPE cells expressed increased levels of PD-L1 in response to IL-17, IFN-γ, or Poly I:C. These PD-L1(hi) RPE cells inhibited the pathogenic activities of IRBP-specific T cells, which usually induced uveitis when injected into naïve mice (EAU). The suppressed pathogenicity of these uveitogenic T cells after exposure to PD-L1(hi) RPE cells could be partially reversed by anti-PD-L1 antibodies. Nevertheless, IRBP-specific T cells pre-exposed to PD-L1(hi) RPE cells displayed substantial suppressor activity, which strongly inhibited the activation of fresh IRBP-Teffs in response to subsequent antigenic challenge and when transferred into naïve mice, inhibited the induction of EAU by IRBP-Teff transfer. These findings suggest that inflammatory cytokine-triggered up-regulation of PD-L1 on RPE constitutes a critical factor for inducing infiltrated uveitogenic T cells with regulatory activities, which may accelerate the natural resolution of T cell-mediated intraocular inflammation.
我们之前报道过，在受到白细胞介素 17（IL-17）和干扰素-γ（IFN-γ）等炎性细胞因子的刺激后，RPE 细胞表达的细胞因子信号转导抑制物（SOCS）增加，从而导致炎症反应受到普遍抑制。在这里，我们证明 RPE 细胞在受到白细胞介素 17（IL-17）、干扰素-γ（IFN-γ）或聚肌苷酸（Poly I:C）的刺激后表达的 PD-L1 水平增加。这些 PD-L1（高表达）RPE 细胞抑制了 IRBP 特异性 T 细胞的致病活性，当将这些 T 细胞注射到未致敏的小鼠（EAE）中时，通常会引起葡萄膜炎。经 PD-L1（高表达）RPE 细胞处理后，这些致葡萄膜炎 T 细胞的致病性被部分逆转，可通过抗 PD-L1 抗体逆转。然而，预先与 PD-L1（高表达）RPE 细胞共孵育的 IRBP 特异性 T 细胞表现出显著的抑制活性，强烈抑制了新鲜的 IRBP-Teff 对随后抗原刺激的激活，并且当转移到未致敏的小鼠中时，抑制了 IRBP-Teff 转移诱导的 EAE。这些发现表明，RPE 上炎性细胞因子触发的 PD-L1 上调构成了诱导具有调节活性的浸润性致葡萄膜炎 T 细胞的关键因素，这可能加速了 T 细胞介导的眼内炎症的自然消退。
