Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, Radboudumc. P.O. Box 9101, 6500 HB, Nijmegen, Netherlands.
Department of Dermatology, Radboud University Medical Center, Radboudumc. P.O. Box 9101, 6500 HB, Nijmegen, Netherlands.
J Immunol Res. 2020 May 14;2020:7680131. doi: 10.1155/2020/7680131. eCollection 2020.
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 , is poorly understood. Therefore, we here evaluated the effect of human Treg injection on cutaneous inflammatory processes using a humanized mouse model of human skin inflammation (huPBL-SCID-huSkin).
SCID beige mice were transplanted with human skin followed by intraperitoneal (IP) injection of 20-40 × 10 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. -expanded human Treg were infused intraperitoneally. Human cutaneous inflammation and systemic immune responses were analysed by immunohistochemistry and flow cytometry.
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 IFN and IL-17A-expressing human T cells, while a trend towards enrichment of FOXP3+ Treg was observed.
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.
最近使用调节性 T 细胞（Treg）的临床试验支持 Treg 为基础的疗法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 Treg 对炎症组织的影响，以及它们对免疫效应功能的影响，仍知之甚少。因此，我们在此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 注射对皮肤炎症过程的影响。
SCID beige 小鼠接受人皮肤移植，然后腹腔内（IP）注射 20-40×10 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）和真皮炎症标志物的变化，如抗菌肽 hBD2 和表皮屏障细胞角蛋白 K10 和 K16，以及真皮中的 T 细胞浸润。腹腔内输注扩增的人类 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。
我们证实，人类 Treg 注射可抑制皮肤炎症和效应 T 细胞的浸润。作为一个新的发现，我们证明人类 Treg 注射导致 IL-17 分泌细胞减少，同时促进人类皮肤中免疫抑制性 FOXP3+Treg 的相对增加，表明在控制局部促炎反应中存在主动免疫调节。与局部控制（皮肤）一致，系统（脾细胞），我们观察到 Treg 注射导致表达 IFN 和 IL-17A 的人类 T 细胞频率降低，而 FOXP3+Treg 呈富集趋势。
综上所述，我们证明 Treg 输注抑制皮肤炎症，除了减少浸润的效应 T 细胞外，还通过恢复细胞因子产生效应 T 细胞和免疫调节 T 细胞之间的局部和全身平衡来介导。这项工作加深了我们对 Treg 为基础免疫疗法的理解。
