Background

Neutrophilic asthma is associated with disease severity and corticosteroid insensitivity. Novel therapies are required to manage this life-threatening asthma phenotype. Programmed cell death protein-1 (PD-1) is a key homeostatic modulator of the immune response for T-cell effector functions.

Objective

We sought to investigate the role of PD-1 in the regulation of acute neutrophilic inflammation in a murine model of airway hyperreactivity (AHR).

Methods

House dust mite was used to induce and compare neutrophilic AHR in wild-type and PD-1 knockout mice. Then, the therapeutic potential of a human PD-1 agonist was tested in a humanized mouse model in which the PD-1 extracellular domain is entirely humanized. Single-cell RNA sequencing and flow cytometry were mainly used to investigate molecular and cellular mechanisms.

Results

PD-1 was highly induced on pulmonary T cells in our inflammatory model. PD-1 deficiency was associated with an increased neutrophilic AHR and high recruitment of inflammatory cells to the lungs. Consistently, PD-1 agonist treatment dampened AHR, decreased neutrophil recruitment, and modulated cytokine production in a humanized PD-1 mouse model. Mechanistically, we demonstrated at the transcriptional and protein levels that the inhibitory effect of PD-1 agonist is associated with the reprogramming of pulmonary effector T cells that showed decreased number and activation.

Conclusions

PD-1 agonist treatment is efficient in dampening neutrophilic AHR and lung inflammation in a preclinical humanized mouse model.

中文翻译：

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人 PD-1 激动剂治疗通过重编程 T 细胞缓解中性粒细胞性哮喘

 背景

中性粒细胞性哮喘与疾病严重程度和皮质类固醇不敏感有关。需要新的疗法来控制这种危及生命的哮喘表型。程序性细胞死亡蛋白-1 (PD-1) 是 T 细胞效应功能免疫反应的关键稳态调节剂。

 客观的

我们试图在气道高反应性 (AHR) 小鼠模型中研究 PD-1 在调节急性中性粒细胞炎症中的作用。

 方法

使用屋尘螨诱导并比较野生型和 PD-1 敲除小鼠的中性粒细胞 AHR 。然后，在人源化小鼠模型中测试了人 PD-1 激动剂的治疗潜力，其中 PD-1 胞外结构域完全人源化。单细胞RNA测序和流式细胞术主要用于研究分子和细胞机制。

 结果

在我们的炎症模型中，肺 T 细胞高度诱导 PD-1。 PD-1 缺乏与中性粒细胞 AHR 增加和肺部炎症细胞大量募集有关。在人源化 PD-1 小鼠模型中，PD-1 激动剂治疗可抑制 AHR、减少中性粒细胞募集并调节细胞因子的产生。从机制上讲，我们在转录和蛋白质水平上证明了 PD-1 激动剂的抑制作用与肺效应 T 细胞的重编程相关，肺效应 T 细胞的数量和激活减少。

 结论

在临床前人源化小鼠模型中，PD-1 激动剂治疗可有效抑制中性粒细胞 AHR 和肺部炎症。