Qihai Team from the Medical School Collaborates to Unveil a New Immunological Mechanism of Allergic Inflammation, Identifying the "True Culprit" Behind Stubborn Chronic Nasal Diseases - Tsinghua University

**Abstract:** A groundbreaking study published in *Nature* on January 16, 2024, by a collaborative team from Tsinghua University and Beijing Tongren Hospital has identified a novel immune mechanism underlying chronic rhinosinusitis with nasal polyps (CRSwNP), a prevalent and recurrent allergic disease. The research, led by Professor Hai Qi from Tsinghua University's School of Medicine, Professor Luo Zhang from the Department of Otolaryngology-Head and Neck Surgery at Beijing Tongren Hospital, and Associate Professor Jianbin Wang from Tsinghua University's School of Life Sciences, reveals a unique subset of memory CD8+ T cells that express granzyme K (GZMK) and play a critical role in the recurrence of airway inflammatory diseases. **Key Events and Discoveries:** 1. **Identification of GZMK-expressing CD8+ T Cells:** - The team analyzed nasal polyp tissues from patients and discovered a distinct population of memory CD8+ T cells that secrete GZMK instead of the conventional granzyme B. - These cells were consistently present in the polyp tissues during each recurrence of the disease, suggesting a pivotal role in the inflammatory process. 2. **Mechanism of GZMK in Disease Recurrence:** - GZMK, unlike granzyme B, can directly activate the complement system without the need for antibodies. - This activation exacerbates tissue damage and intensifies the inflammatory response, leading to the chronic and recurrent nature of CRSwNP. - The cells are highly active, continuously migrating from peripheral blood to nasal tissues, which perpetuates the disease cycle. 3. **Potential Therapeutic Target:** - The study explored the possibility of treating CRSwNP by inhibiting GZMK. - Animal experiments demonstrated that clearing or inhibiting GZMK in CD8+ T cells significantly reduced inflammation and improved treatment outcomes. - These findings suggest that GZMK and the GZMK-expressing memory CD8+ T cells could serve as important biomarkers for disease progression and therapeutic response. **Implications and Future Directions:** - The identification of GZMK as a new drug target offers a promising avenue for developing more effective and safer treatments for CRSwNP and other allergic diseases. - Professor Qi emphasized the integration of basic research and clinical application, noting that the team has identified candidate inhibitors for GZMK and is progressing with drug development through technology transfer. - Professor Zhang highlighted the importance of solving clinical problems and expressed a desire to expedite the process, aiming to initiate rigorous clinical trials to bring the new treatment options to patients. **Collaborative Effort and Support:** - The research was a collaborative effort involving multiple institutions and researchers, including Tsinghua University and Beijing Tongren Hospital. - Key contributors to the study include researchers Feng Lan, Jizhou Li, Wenhuan Miao, and Fei Sun, who are listed as co-first authors. - The study was supported by the National Key Research and Development Program, Tsinghua University's Independent Research Program, the National Natural Science Foundation of China, the Shanxi Medical University-Tsinghua University School of Medicine Frontier Medical Biotechnology Research Program, and the National Health Commission and the New Foundation for Science. **Conclusion:** This pioneering research provides a new immunological mechanism for chronic and recurrent airway inflammatory diseases, particularly CRSwNP. By identifying GZMK-expressing memory CD8+ T cells and their role in disease recurrence, the study opens the door to innovative therapeutic strategies. The findings not only advance the scientific understanding of these conditions but also position Chinese researchers at the forefront of international efforts in this field. The potential for developing targeted drugs to inhibit GZMK could significantly improve the quality of life for millions of patients suffering from chronic nasal diseases and related allergic conditions. **Paper Link:** https://www.nature.com/articles/s41586-024-08395-9 **Source:** Tsinghua University School of Medicine **Editors:** Xiao Ling, Guo Ling