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

Feng Lan, Jizhou Li, Wenxuan Miao, Fei Sun, Su Duan, Yabing Song, Jiacheng Yao, Xiangdong Wang, Chengshuo Wang, Xin Liu (), Jianbin Wang (), Luo Zhang () and Hai Qi ()
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Feng Lan: Capital Medical University
Jizhou Li: Tsinghua-Peking Center for Life Sciences
Wenxuan Miao: Tsinghua University
Fei Sun: Tsinghua University
Su Duan: Beijing Institute of Otolaryngology
Yabing Song: Tsinghua University
Jiacheng Yao: Changping Laboratory
Xiangdong Wang: Capital Medical University
Chengshuo Wang: Capital Medical University
Xin Liu: Tsinghua University
Jianbin Wang: Tsinghua University
Luo Zhang: Capital Medical University
Hai Qi: Tsinghua University

Nature, 2025, vol. 638, issue 8050, 490-498

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-024-08395-9

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