程序性细胞死亡 1 (PD-1) 表达不仅与 T 细胞激活相关，还与细胞耗竭相关。具体而言，PD-1 T 细胞在慢性抗原暴露条件下（例如肿瘤微环境和慢性病毒感染）呈现出耗尽的表型。然而，包括特发性炎症性肌病 (IIM) 在内的慢性自身免疫性疾病中 PD-1 CD8 T 细胞耗竭的免疫状态仍不清楚。我们的目的是阐明 PD-1 CD8 T 细胞和 PD-1 配体 (PD-L1) 在 IIM 中的作用。我们发现，PD-1 细胞浸润到 IIM 和免疫检查点抑制剂相关肌病患者表达 PD-L1 的肌肉中。根据外周血免疫表型分析，活动患者和非活动患者的 PD-1 CD8 细胞比例相当。值得注意的是，活动患者中的 PD-1 CD8 细胞高表达溶细胞分子，表明其激活，而活动患者和非活动患者中的 PD-1-CD8 细胞表达低水平的溶细胞分子。活动期患者部分PD-1 CD8细胞高表达HMG-box转录因子TOX并呈现疲惫表型。在PD-1 CD4 T细胞中，PD-1highCXCR5-CD45RO CD4外周辅助T细胞在活跃患者中增加。 PD-L1缺陷小鼠出现更严重的C蛋白诱导性肌炎（CIM），这是一种多发性肌炎模型，与野生型小鼠相比，表达细胞溶解分子的PD-1 CD8细胞浸润更丰富，表明PD-1 CD8细胞具有致病性以及PD-L1的保护作用。 IFNγ（一种通用的 PD-L1 诱导剂）的缺乏会导致肌肉 PD-L1 表达受损并加剧 CIM，表明 IFNγ 依赖性肌肉 PD-L1 调节。在已建立的肌肉损伤模型中，肌管上的 IFNγ 诱导的 PD-L1 具有保护作用。总之，PD-1 CD8 T 细胞而不是 PD-1-CD8 T 细胞是 IIM 的致病子集。肌肉 PD-L1 受 IFNγ 调节，并在 IIM 中发挥保护特性。版权所有 © 2023 Elsevier Ltd。保留所有权利。

Programmed-cell-death 1 (PD-1) expression is associated not only with T-cell activation but with exhaustion. Specifically, PD-1+ T cells present an exhausted phenotype in conditions of chronic antigen exposure, such as tumor microenvironments and chronic viral infection. However, the immune status regarding exhaustion of PD-1+CD8+ T cells in chronic autoimmune diseases including idiopathic inflammatory myopathies (IIMs) remains unclear. We aimed to clarify the role of PD-1+CD8+ T cells and PD-1 ligand (PD-L1) in IIMs. We showed that PD-1+ cells infiltrated into PD-L1-expressing muscles in patients with IIMs and immune checkpoint inhibitor-related myopathy. According to the peripheral blood immunophenotyping, the PD-1+CD8+ cell proportions were comparable between the active and inactive patients. Of note, PD-1+CD8+ cells in the active patients highly expressed cytolytic molecules, indicating their activation, while PD-1-CD8+ cells expressed low levels of cytolytic molecules in the active and inactive patients. A part of PD-1+CD8+ cells expressed the HMG-box transcription factor TOX highly and presented the exhausted phenotype in the active patients. Among PD-1+CD4+ T cells, PD-1highCXCR5-CD45RO+CD4+ peripheral helper T cells were increased in the active patients. PD-L1-deficient mice developed severer C-protein-induced myositis (CIM), a model of polymyositis, with abundant infiltration of PD-1+CD8+ cells expressing cytolytic molecules than wild-type mice, indicating pathogenicity of the PD-1+CD8+ cells and the protective role of PD-L1. The deficiency of IFNγ, a general PD-L1-inducer, impaired muscular PD-L1 expression and exacerbated CIM, indicating IFNγ-dependent muscular PD-L1 regulation. IFNγ-induced PD-L1 on myotubes was protective in an established muscle injury model. In conclusion, PD-1+CD8+ T cells rather than PD-1-CD8+ T cells were a pathogenic subset of IIMs. Muscular PD-L1 was regulated by IFNγ and exerted protective properties in IIMs.Copyright © 2023 Elsevier Ltd. All rights reserved.