ABSTRACT

Background: T cells present in chronic inflammatory tissues such as nasal polyps (from chronic rhinosinusitis patients) have been demonstrated to be hypo-responsive to activation via the TCR, similar to tumor-specific T cells in multiple different human tumor microenvironments. While immunosuppressive exosomes have been known to contribute to the failure of the tumor-associated T cells to respond optimally to activation stimuli, it is not known whether they play a similar role in chronic inflammatory microenvironments. In the current study, we investigate whether exosomes derived from chronic inflammatory microenvironments contribute to the immune suppression of T cells.

Methods: Exosomes were isolated by ultracentrifugation and characterized by size and composition using nanoparticle tracking analysis, scanning electron microscopy, antibody arrays and flow exometry. Immunosuppressive ability of the exosomes was measured by quantifying its effect on activation of T cells, using nuclear translocation of NFκB as an activation endpoint.

Results: Exosomes were isolated and characterized from two different types of chronic inflammatory tissues – nasal polyps from chronic rhinosinusitis patients and synovial fluid from rheumatoid arthritis patients. These exosomes arrest the activation of T cells stimulated via the TCR. This immune suppression, like that which is seen in tumor microenvironments, is dependent in part upon a lipid, ganglioside GD3, which is expressed on the exosomal surface.

Conclusion: Immunosuppressive exosomes present in non-malignant chronic inflammatory tissues represent a new T cell checkpoint, and potentially represent a novel therapeutic target to enhance the response to current therapies and prevent disease recurrences.

摘要

背景：存在于鼻息肉（来自慢性鼻窦炎患者）等慢性炎症组织中的 T 细胞已被证明对通过 TCR 的激活反应低下，类似于多种不同人类肿瘤微环境中的肿瘤特异性 T 细胞。虽然已知免疫抑制性外泌体会导致肿瘤相关 T 细胞无法对激活刺激做出最佳反应，但尚不清楚它们是否在慢性炎症微环境中发挥类似作用。在当前的研究中，我们研究了源自慢性炎症微环境的外泌体是否有助于 T 细胞的免疫抑制。

方法：通过超速离心法分离外泌体，并使用纳米粒子追踪分析、扫描电子显微镜、抗体阵列和流式外泌体对大小和组成进行表征。外泌体的免疫抑制能力是通过量化其对 T 细胞活化的影响来测量的，使用 NFκB 的核转位作为活化终点。

结果：从两种不同类型的慢性炎症组织——慢性鼻窦炎患者的鼻息肉和类风湿性关节炎患者的滑液中分离并表征了外泌体。这些外泌体阻止了通过 TCR 刺激的 T 细胞的激活。这种免疫抑制，就像在肿瘤微环境中看到的那样，部分取决于在外泌体表面表达的脂质神经节苷脂 GD3。

结论：存在于非恶性慢性炎症组织中的免疫抑制外泌体代表了一个新的 T 细胞检查点，并可能代表一种新的治疗靶点，以增强对当前疗法的反应并预防疾病复发。