ABSTRACT

Excessive and persistent inflammation after injury lead to chronic wounds, increased tissue damage or even aggressive carcinogenic transformation. Effective wound repair could be achieved by inhibiting overactive immune cells to the injured site. In this study, we obtained high concentration of PD-L1 in exosomes from either genetically engineered cells overexpressing PD-L1 or IFN-γ stimulated cells. We found that exosomal PD-L1 is specially bound to PD-1 on T cell surface, and suppressed T cell activation. Interestingly, exosomal PD-L1 promoted the migration of epidermal cells and dermal fibroblasts when pre-incubated with T cells. We further embedded exosomes into thermoresponsive PF-127 hydrogel, which was gelatinized at body temperature to release exosomes to the surroundings in a sustained manner. Of importance, in a mouse skin excisional wound model, exosomal PD-L1 significantly fastened wound contraction and reepithelialization when embedded in hydrogel during inflammation phase. Finally, exosomal PD-L1 inhibited cytokine production of CD8+ T cells and suppressed CD8+ T cell numbers in spleen and peripheral lymph nodes. Taken together, these data provide evidence on exosomal PD-L1 exerting immune inhibitory effects and promoting tissue repair.

抽象的

受伤后过度和持续的炎症会导致慢性伤口，增加的组织损伤，甚至导致严重的致癌性转化。有效的伤口修复可以通过抑制过度活跃的免疫细胞至受伤部位来实现。在这项研究中，我们从过表达PD-L1或IFN-γ刺激的细胞的基因工程细胞中获得了高浓度的PD-L1。我们发现外泌体PD-L1特别绑定到T细胞表面上的PD-1，并抑制了T细胞活化。有趣的是，外泌体PD-L1在与T细胞预孵育后促进了表皮细胞和真皮成纤维细胞的迁移。我们将外泌体进一步嵌入到热响应性PF-127水凝胶中，该凝胶在人体温度下会糊化，从而以持续的方式将外泌体释放到周围环境中。重要的是 在小鼠皮肤切除伤口模型中，外泌体PD-L1在发炎阶段嵌入水凝胶时可显着固定伤口收缩和上皮再形成。最后，外泌体PD-L1抑制了脾脏和外周淋巴结中CD8 + T细胞的细胞因子生成，并抑制了CD8 + T细胞数量。综上所述，这些数据提供了关于外泌体PD-L1发挥免疫抑制作用并促进组织修复的证据。