Background. Recent clinical trials using regulatory T cells (Treg) support the therapeutic potential of Treg-based therapy in transplantation and autoinflammatory diseases. Despite these clinical successes, the effect of Treg on inflamed tissues, as well as their impact on immune effector function in vivo, is poorly understood. Therefore, we here evaluated the effect of human Treg injection on cutaneous inflammatory processes in vivo using a humanized mouse model of human skin inflammation (huPBL-SCID-huSkin). Methods. SCID beige mice were transplanted with human skin followed by intraperitoneal (IP) injection of allogeneic human PBMCs. This typically results in human skin inflammation as indicated by epidermal thickening (hyperkeratosis) and changes in dermal inflammatory markers such as the antimicrobial peptide hBD2 and epidermal barrier cytokeratins K10 and K16, as well as T cell infiltration in the dermis. Ex vivo-expanded human Treg were infused intraperitoneally. Human cutaneous inflammation and systemic immune responses were analysed by immunohistochemistry and flow cytometry. Results. We confirmed that human Treg injection inhibits skin inflammation and the influx of effector T cells. As a novel finding, we demonstrate that human Treg injection led to a reduction of IL-17-secreting cells while promoting a relative increase in immunosuppressive FOXP3+ Treg in the human skin, indicating active immune regulation in controlling the local proinflammatory response. Consistent with the local control (skin), systemically (splenocytes), we observed that Treg injection led to lower frequencies of IFNγ and IL-17A-expressing human T cells, while a trend towards enrichment of FOXP3+ Treg was observed. Conclusion. Taken together, we demonstrate that inhibition of skin inflammation by Treg infusion, next to a reduction of infiltrating effector T cells, is mediated by restoring both the local and systemic balance between cytokine-producing effector T cells and immunoregulatory T cells. This work furthers our understanding of Treg-based immunotherapy.

中文翻译：

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成功的基于 T 细胞的调节性治疗依赖于皮肤炎症人源化小鼠模型中 T 细胞效应功能的抑制和 FOXP3+ 细胞的富集。

背景。最近使用调节性 T 细胞 (Treg) 的临床试验支持基于 Treg 的治疗在移植和自身炎症性疾病中的治疗潜力。尽管取得了这些临床成功，但人们对 Treg 对发炎组织的影响以及它们对体内免疫效应功能的影响知之甚少。因此，我们在这里使用人类皮肤炎症的人源化小鼠模型 (huPBL-SCID-huSkin)评估了人类 Treg 注射对体内皮肤炎症过程的影响。方法。将 SCID 米色小鼠移植到人皮肤上，然后腹膜内 (IP) 注射同种异体人 PBMC。这通常会导致人类皮肤炎症，表现为表皮增厚（角化过度）和真皮炎症标志物（如抗菌肽 hBD2 和表皮屏障细胞角蛋白 K10 和 K16）的变化，以及真皮中的 T 细胞浸润。腹膜内输注离体扩增的人Treg。通过免疫组织化学和流式细胞术分析人类皮肤炎症和全身免疫反应。结果. 我们证实，人 Treg 注射可抑制皮肤炎症和效应 T 细胞的流入。作为一项新发现，我们证明人 Treg 注射导致 IL-17 分泌细胞减少，同时促进人皮肤中免疫抑制性 FOXP3+ Treg 的相对增加，表明主动免疫调节在控制局部促炎反应中。与局部对照（皮肤）、全身（脾细胞）一致，我们观察到 Treg 注射导致表达 IFN γ和 IL-17A 的人类 T 细胞的频率降低，同时观察到 FOXP3+ Treg 富集的趋势。结论. 总之，我们证明了通过 Treg 输注抑制皮肤炎症，以及减少浸润性效应 T 细胞，是通过恢复产生细胞因子的效应 T 细胞和免疫调节 T 细胞之间的局部和全身平衡来介导的。这项工作进一步加深了我们对基于 Treg 的免疫疗法的理解。