2. Academic Validation
  3. GZMK-expressing CD8+ T cells promote recurrent airway inflammatory diseases

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

  • Nature. 2025 Jan 15. doi: 10.1038/s41586-024-08395-9.
Feng Lan # 1 2 3,  Jizhou Li # 4 5,  Wenxuan Miao # 3 6,  Fei Sun # 5,  Su Duan 2 7,  Yabing Song 5,  Jiacheng Yao 8,  Xiangdong Wang 1 2,  Chengshuo Wang 1 2,  Xin Liu 9 10 11,  Jianbin Wang 12 13,  Luo Zhang 14 15 16,  Hai Qi 17 18 19 20 21 22 23 24
Affiliations

Affiliations

  • 1 Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China.
  • 2 Beijing Key Laboratory of Nasal Disease, Beijing Institute of Otolaryngology, Beijing, China.
  • 3 Laboratory of Dynamic Immunobiology, Institute for Immunology, Tsinghua University, Beijing, China.
  • 4 Tsinghua-Peking Center for Life Sciences, Beijing, China.
  • 5 School of Life Sciences, Tsinghua University, Beijing, China.
  • 6 School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University, Beijing, China.
  • 7 Department of Allergy, Beijing TongRen Hospital, Capital Medical University, Beijing, China.
  • 8 Changping Laboratory, Beijing, China.
  • 9 Laboratory of Dynamic Immunobiology, Institute for Immunology, Tsinghua University, Beijing, China. xil2020@tsinghua.edu.cn.
  • 10 School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University, Beijing, China. xil2020@tsinghua.edu.cn.
  • 11 Changping Laboratory, Beijing, China. xil2020@tsinghua.edu.cn.
  • 12 School of Life Sciences, Tsinghua University, Beijing, China. jianbinwang@tsinghua.edu.cn.
  • 13 Changping Laboratory, Beijing, China. jianbinwang@tsinghua.edu.cn.
  • 14 Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China. dr.luozhang@139.com.
  • 15 Beijing Key Laboratory of Nasal Disease, Beijing Institute of Otolaryngology, Beijing, China. dr.luozhang@139.com.
  • 16 Department of Allergy, Beijing TongRen Hospital, Capital Medical University, Beijing, China. dr.luozhang@139.com.
  • 17 Laboratory of Dynamic Immunobiology, Institute for Immunology, Tsinghua University, Beijing, China. qihai@tsinghua.edu.cn.
  • 18 Tsinghua-Peking Center for Life Sciences, Beijing, China. qihai@tsinghua.edu.cn.
  • 19 School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University, Beijing, China. qihai@tsinghua.edu.cn.
  • 20 Changping Laboratory, Beijing, China. qihai@tsinghua.edu.cn.
  • 21 New Cornerstone Science Laboratory, Tsinghua Medicine, Tsinghua University, Beijing, China. qihai@tsinghua.edu.cn.
  • 22 Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China. qihai@tsinghua.edu.cn.
  • 23 Beijing Key Laboratory for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China. qihai@tsinghua.edu.cn.
  • 24 SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, China. qihai@tsinghua.edu.cn.
  • # Contributed equally.
PMID: 39814882 DOI: 10.1038/s41586-024-08395-9
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.

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