PD-L1 on mast cells suppresses effector CD8+ T-cell activation in the skin in murine contact hypersensitivity
PD-L1 on mast cells suppresses effector CD8+ T-cell activation in the skin in murine contact hypersensitivity
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DOI：
10.1016/j.jaci.2020.12.654
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发表时间：
2021-08-04
影响因子：
14.2
通讯作者：
Kabashima, Kenji
中科院分区：
文献类型：
--
作者：
Hirano, Tomoko;Honda, Tetsuya;Kabashima, Kenji
背景：已知的程序性细胞死亡-1(PD-1)/程序性死亡配体1(PD-L1)通路可抑制效应CD8(+)T细胞的激活。目的：探讨PD-1/PD-L1通路在CD8(+)T细胞介导的皮肤免疫应答中的调节作用机制。方法：采用PD-L1基因缺陷(PDL1(-/-))小鼠建立接触性超敏反应模型。结果：与野生型小鼠相比，PDL1(-/-)小鼠耳肿胀加重，皮肤中干扰素-γ(+)CD8(+)T细胞数量增加。过继T细胞转移实验显示PD-1/PD-L1通路参与了接触性超敏反应的诱发阶段。骨髓嵌合体实验表明，辐射抵抗细胞上的PD-L1负责这一调控途径。流式细胞仪分析表明，在皮肤中的抗辐射细胞中，PD-L1在诱导前后的肥大细胞(MC)上表达最高。在诱导期给予抗PD-L1封闭抗体可显著增强野生型小鼠的耳肿胀反应，增加皮肤中干扰素-γ(+)CD8(+)T细胞的数量，而MC缺陷小鼠(WBB6F1/J-Kit(W)/Kit(W-v)/J和C57BL/6-KitW(-sh)/W-sh)对此无明显影响。数据库分析和免疫组织化学分析证实PD-L1在人皮肤MCs上的高表达。结论：MCs上的PD-L1对皮肤CD8(+)T细胞的激活具有负性调节作用。
Background: The programmed cell death-1 (PD-1)/programmed death ligand 1 (PD-L1) pathway is known to inhibit the activation of effector CD8(+) T cells. However, just how this regulatory pathway is involved in the pathophysiology of CD8(+) T-cell-mediated inflammatory skin diseases remains unclear.Objective: Our aim was to elucidate the mechanisms by which the PD-1/PD-L1 pathway exerts its regulatory roles in CD8(+) T-cell-mediated cutaneous immune responses.Methods: PD-L1-deficient (Pdl1(-/-)) mice were used for the murine contact hypersensitivity model. Inflammatory responses such as IFN-gamma production from CD8(+) T cells in the skin was evaluated by flow cytometry.Results: Compared with wild-type mice, Pdl1(-/-) mice exhibited exacerbated ear swelling and increased numbers of IFN-gamma(+) CD8(+) T cells in the skin. Adoptive T-cell transfer experiments revealed the involvement of the PD-1/PD-L1 pathway in the elicitation phase of contact hypersensitivity. Bone marrow chimera experiments showed that PD-L1 on radioresistant cells was responsible for this regulatory pathway. Flow cytometric analysis revealed that among the radioresistant cells in the skin, PD-L1 was most highly expressed on mast cells (MCs) before and after elicitation. Administration of anti-PD-L1 blocking antibody during the elicitation phase significantly enhanced ear swelling responses and increased the number of IFN-gamma(+)CD8(+) T cells in the skin of wild-type mice, whereas no significant effects were observed in MC-deficient (WBB6F1/J-Kit(W)/Kit(W-v)/J and C57BL/6-KitW(-sh)/W-sh) mice. The high level of expression of PD-L1 on human skin MCs was confirmed by database analysis and immunohistochemical analysis.Conclusion: PD-L1 on MCs negatively regulates CD8(+) T-cell activation in the skin.