Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.
Cell Death Dis. 2024 Sep 30;15(9):705. doi: 10.1038/s41419-024-07080-z.
Asthma is a chronic airway inflammatory disease in which CD4 T cell dysregulation occurs. Here, we investigated the molecular role and clinical significance of CD226, a costimulatory molecule of T lymphocytes, in the development of allergic asthma. Our results revealed that the expression of CD226 was significantly increased in CD4 effector T cells, especially in T helper (Th) 2 cells and Th17 cells in patients with asthma. Moreover, CD4 T cell-specific Cd226-knockout mice were generated and together with littermates were challenged with ovalbumin (OVA) to establish a model of allergic asthma. We found that CD226 deficiency in CD4 T cells mitigated lung inflammation, IgE production, and eosinophil infiltration and reduced airway remodeling in experimental allergic asthma. However, the impact of CD226 on asthma was independent of Treg cell modulation. Through RNA-seq data analysis, the apoptosis pathway was screened. Mechanistically, CD226 deletion promoted CD4 T cell late apoptosis via the activation of Caspase-3 in an Akt-dependent manner. Furthermore, blocking CD226 signaling with a recombinant fusion protein attenuated asthma features in mice and achieved a good therapeutic effect. Overall, this study revealed a unique role of CD226 in CD4 T cell regulation in asthma pathogenesis. Therefore, targeting CD226 may provide new insights into the clinical treatment of asthma.
哮喘是一种慢性气道炎症性疾病，其中发生 CD4 T 细胞失调。在这里，我们研究了淋巴细胞共刺激分子 CD226 在过敏性哮喘发展中的分子作用和临床意义。我们的结果表明，哮喘患者 CD4 效应 T 细胞（尤其是辅助性 T 细胞（Th）2 细胞和 Th17 细胞）中 CD226 的表达显著增加。此外，还生成了 CD4 T 细胞特异性 Cd226 敲除小鼠，并与同窝仔鼠一起用卵清蛋白（OVA）进行攻毒以建立过敏性哮喘模型。我们发现 CD226 缺失可减轻实验性过敏性哮喘中的肺部炎症、IgE 产生和嗜酸性粒细胞浸润，并减少气道重塑。然而，CD226 对哮喘的影响与 Treg 细胞调节无关。通过 RNA-seq 数据分析，筛选出了凋亡途径。从机制上讲，CD226 缺失通过 Akt 依赖性激活 Caspase-3 促进 CD4 T 细胞晚期凋亡。此外，用重组融合蛋白阻断 CD226 信号可减轻哮喘小鼠的特征，并取得良好的治疗效果。总的来说，这项研究揭示了 CD226 在哮喘发病机制中对 CD4 T 细胞调节的独特作用。因此，靶向 CD226 可能为哮喘的临床治疗提供新的思路。
