Department of Pediatrics, University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
J Virol. 2024 Oct 22;98(10):e0079724. doi: 10.1128/jvi.00797-24. Epub 2024 Sep 23.
A key mediator of T cell impairment during respiratory virus infection is the inhibitory receptor PD-1. PD-1 is induced on T cells following antigen exposure, whereas proinflammatory cytokines upregulate the ligands PD-L1 and PD-L2. Respiratory virus infection leads to upregulation of PD-L1 on airway epithelial cells, dendritic cells, and alveolar macrophages. However, the role of PD-L1 on different cell types in acute respiratory virus infections is not known. We sought to determine the role of PD-L1 on different cell types in CD8 T cell impairment. We found that PD-L1 mice challenged with human metapneumovirus or influenza showed a similar level of CD8 T cell impairment compared to wild-type (WT) mice. Moreover, virus clearance was delayed in PD-L1 mice compared to WT. CD8 T cells from PD-L1-deficient mice expressed higher levels of inhibitory receptors both at baseline and after respiratory virus infection. The antibody blockade of PD-L2 failed to restore function to the impaired cells. While reciprocal bone marrow chimeras between WT and PD-L1 mice did not restore CD8 T cell function after the respiratory virus challenge, mice that received the PD-L1 bone marrow had higher inhibitory receptor expression on CD8 cells. This discrepancy in the inhibitory receptor expression suggests that cells of the hematopoietic compartment contribute to T cell impairment on CD8 T cells.IMPORTANCEThe phenomenon of pulmonary CD8 T cell impairment with diminished antiviral function occurs during acute respiratory virus infection mediated by Programmed Cell Death-1 (PD-1) signaling. Moreover, PD-1 blockade enhances T cell function to hasten viral clearance. The ligand PD-L1 is expressed in many cell types, but which cells drive lung T cell impairment is not known. We used genetic approaches to determine the contribution of PD-L1 on lung T cell impairment. We found that PD-L2 cannot compensate for the loss of PD-L1, and PD-L1-deficient mice exhibit increased expression of other inhibitory receptors. Bone marrow chimeras between PD-L1-deficient and wild-type mice indicated that hematopoietic PD-L1 expression is associated with inhibitory receptor upregulation and impairment.
细胞程序性死亡蛋白-1（PD-1）信号通路介导了呼吸道病毒感染期间 T 细胞功能障碍。T 细胞在抗原暴露后诱导 PD-1，而促炎细胞因子上调 PD-L1 和 PD-L2 的配体。呼吸道病毒感染导致气道上皮细胞、树突状细胞和肺泡巨噬细胞 PD-L1 的上调。然而，在急性呼吸道病毒感染中，不同细胞类型上 PD-L1 的作用尚不清楚。我们试图确定 PD-L1 在不同细胞类型对 CD8 T 细胞功能障碍的作用。我们发现，与人偏肺病毒或流感病毒感染的 PD-L1 敲除小鼠与野生型（WT）小鼠相比，CD8 T 细胞损伤程度相似。此外，PD-L1 敲除小鼠的病毒清除延迟。PD-L1 缺陷小鼠的 CD8 T 细胞在基线和呼吸道病毒感染后表达更高水平的抑制性受体。PD-L2 抗体阻断未能恢复受损细胞的功能。虽然 WT 和 PD-L1 小鼠之间的骨髓嵌合体在呼吸道病毒挑战后没有恢复 CD8 T 细胞的功能，但接受 PD-L1 骨髓的小鼠的 CD8 细胞上表达更高水平的抑制性受体。这种抑制性受体表达的差异表明造血细胞对 CD8 T 细胞的 T 细胞损伤有贡献。
重要性在呼吸道病毒感染过程中，细胞程序性死亡蛋白-1（PD-1）信号介导的肺部 CD8 T 细胞功能障碍，导致抗病毒功能减弱。此外，PD-1 阻断增强 T 细胞功能以加速病毒清除。PD-L1 的配体在许多细胞类型中表达，但哪些细胞驱动肺部 T 细胞损伤尚不清楚。我们使用遗传方法来确定 PD-L1 对肺部 T 细胞损伤的贡献。我们发现 PD-L2 不能补偿 PD-L1 的缺失，PD-L1 缺陷小鼠表现出其他抑制性受体的表达增加。PD-L1 缺陷型和野生型小鼠之间的骨髓嵌合体表明，造血 PD-L1 表达与抑制性受体上调和损伤有关。
