清华大学祁海等研究人员合作发现，GZMK表达的CD8⁺ T细胞促进复发性气道炎症性疾病。该研究于2025年1月15日在线发表于国际一流学术期刊《自然》。

通过比较来自连续手术的鼻息肉组织中的T细胞库，研究人员报告了在疾病复发过程中，带有效应记忆样特征的持久性CD8⁺ T细胞克隆定植在黏膜组织中，这些细胞特征性地表达胰蛋白酶Granzyme K（GZMK）。研究人员发现，GZMK切割多种补体成分，包括C2、C3、C4和C5，这些成分共同促进了补体级联反应的激活。GZMK表达的CD8⁺ T细胞参与了有组织的三级淋巴结构，组织中GZMK水平比已知的生物标志物，如嗜酸性粒细胞增多症和组织间质细胞因子5，更能预测疾病的严重性和合并症。

使用小鼠哮喘模型，研究人员进一步表明，GZMK表达的CD8⁺ T细胞通过GZMK和补体的蛋白酶活性加重了疾病。疾病发作后，通过基因敲除或药物抑制GZMK，可显著缓解组织病理并恢复肺功能。该研究确定了一种致病性的CD8⁺记忆T细胞亚群，GZMK作为效应分子促进了组织炎症和复发性气道疾病，并提出GZMK作为潜在的治疗靶点。

据悉，炎症性疾病通常是慢性且复发性的，当前的治疗方法通常无法去除潜在的疾病驱动因素。T细胞参与了广泛的炎症性疾病，如银屑病、克罗恩病、食管炎和多发性硬化症，且克隆性扩展的抗原特异性T细胞可能部分通过形成持久的致病性记忆，促进疾病的慢性化和复发。慢性鼻窦炎和哮喘是常见的气道炎症性疾病，且常作为合并症出现。慢性鼻窦炎影响超过10%的普通人群。在这些患者中，20-25%会发展为鼻息肉，这通常由于复发率高需要反复手术切除。虽然大量T细胞浸润鼻息肉组织，但驱动疾病病理并促进复发的T细胞亚群尚不完全清楚。

附：英文原文

Title: GZMK-expressing CD8+ T cells promote recurrent airway inflammatory diseases

Author: Lan, Feng, Li, Jizhou, Miao, Wenxuan, Sun, Fei, Duan, Su, Song, Yabing, Yao, Jiacheng, Wang, Xiangdong, Wang, Chengshuo, Liu, Xin, Wang, Jianbin, Zhang, Luo, Qi, Hai

Issue&Volume: 2025-01-15

Abstract: Inflammatory diseases are often chronic and recurrent, and current treatments do not typically remove underlying disease drivers1. T cells participate in a wide range of inflammatory diseases such as psoriasis2, Crohn’s disease3, oesophagitis4 and multiple sclerosis5,6, and clonally expanded antigen-specific T cells may contribute to disease chronicity and recurrence, in part by forming persistent pathogenic memory. Chronic rhinosinusitis and asthma are inflammatory airway diseases that often present as comorbidities7. Chronic rhinosinusitis affects more than 10% of the general population8. Among these patients, 20–25% would develop nasal polyps, which often require repeated surgical resections owing to a high incidence of recurrence9. Whereas abundant T cells infiltrate the nasal polyps tissue10,11, T cell subsets that drive the disease pathology and promote recurrence are not fully understood. By comparing T cell repertoires in nasal polyp tissues obtained from consecutive surgeries, here we report that persistent CD8+ T cell clones carrying effector memory-like features colonize the mucosal tissue during disease recurrence, and these cells characteristically express the tryptase Granzyme K (GZMK). We find that GZMK cleaves many complement components, including C2, C3, C4 and C5, that collectively contribute to the activation of the complement cascade. GZMK-expressing CD8+ T cells participate in organized tertiary lymphoid structures, and tissue GZMK levels predict the disease severity and comorbidities better than well-established biomarkers such as eosinophilia and tissue interleukin-5. Using a mouse asthma model, we further show that GZMK-expressing CD8+ T cells exacerbate the disease in a manner dependent on the proteolytic activity of GZMK and complements. Genetic ablation or pharmacological inhibition of GZMK after the disease onset markedly alleviates tissue pathology and restores lung function. Our work identifies a pathogenic CD8+ memory T cell subset that promotes tissue inflammation and recurrent airway diseases by the effector molecule GZMK and suggests GZMK as a potential therapeutic target.

DOI: 10.1038/s41586-024-08395-9

Source: https://www.nature.com/articles/s41586-024-08395-9