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Cytotoxic T cells meet complement: granzyme K as a new initiator of inflammation

Cellular & Molecular Immunology volume 22, pages 693–695 (2025)Cite this article

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Historically, three pathways have been shown to activate the complement cascade. Recently, Lan et al. and Donado et al. independently reported that granzyme K expressed by CD8+ T cells is capable of cleaving complement proteins C4 and C2 to activate the complement cascade.

The complement system is an ancient immune defense mechanism involving more than 30 plasma proteins, which are produced primarily by the liver [1]. Complement proteins are normally inactive, and three pathways activate the complement cascade: the classical pathway (triggered by antibody‒antigen complexes), the lectin pathway (initiated by microbial glycoprotein binding), and the alternative pathway (involving the complement factor D protease). All three pathways converge at the assembly of C3 convertase and then C5 convertase. Downstream effects include membrane attack complex formation, opsonization (e.g., C3b), and inflammation (via C3a/C5a) [2], collectively contributing to host antipathogen defense. However, excessive complement activation can damage host tissues, exacerbating autoimmune and inflammatory diseases such as rheumatoid arthritis and lupus [3], but the triggers for complement activation in those diseases are largely unknown.

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References

  1. Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11:785–97. https://doi.org/10.1038/ni.1923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lo MW, Woodruff TM. Complement: Bridging the innate and adaptive immune systems in sterile inflammation. J Leukoc Biol. 2020;108:339–51. https://doi.org/10.1002/JLB.3MIR0220-270R.

    Article  CAS  PubMed  Google Scholar 

  3. Coss SL, Zhou D, Chua GT, Aziz RA, Hoffman RP, Wu YL et al. The complement system and human autoimmune diseases. J Autoimmun. 2023;137:102979. https://doi.org/10.1016/j.jaut.2022.102979.

    Article  CAS  PubMed  Google Scholar 

  4. Anthony DA, Andrews DM, Watt SV, Trapani JA, Smyth MJ. Functional dissection of the granzyme family: cell death and inflammation. Immunological Rev. 2010;235:73–92. https://doi.org/10.1111/j.0105-2896.2010.00907.x.

    Article  CAS  Google Scholar 

  5. Gordy C, He Y-W. Endocytosis by target cells: an essential means for perforin- and granzyme-mediated killing. Cell Mol Immunol. 2012;9:5–6. https://doi.org/10.1038/cmi.2011.45.

    Article  PubMed  Google Scholar 

  6. Bouwman AC, van Daalen KR, Crnko S, ten Broeke T, Bovenschen N. Intracellular and Extracellular Roles of Granzyme K. Front Immunol. 2021;12. https://doi.org/10.3389/fimmu.2021.677707.

  7. Lan F, Li J, Miao W, Sun F, Duan S, Song Y et al. GZMK-expressing CD8+ T cells promote recurrent airway inflammatory diseases. Nature. 2025;638:490–8. https://doi.org/10.1038/s41586-024-08395-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Donado CA, Theisen E, Zhang F, Nathan A, Fairfield ML, Rupani KV et al. Granzyme K activates the entire complement cascade. Nature. 2025;641:211–21. https://doi.org/10.1038/s41586-025-08713-9.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the Liu and Li lab members for their discussions during the preparation of this manuscript.

Funding

Supported by a Shenzhen Medical Research Fund (Conglei Li), grant number B2402012; Shenzhen Science and Technology Program (Conglei Li), grant number JCYJ20220530143417039; Guangdong Basic and Applied Basic Research Foundation (Conglei Li), grant number 2024A1515013185; and the National Science Fund of China (Conglei Li), grant number 82271789.

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Authors and Affiliations

  1. School of Medicine, The Chinese University of Hong Kong, Shenzhen, China

    Junyi Zhao & Conglei Li

  2. State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, Ministry of Education Key Laboratory of Protein Sciences, Tsinghua University, Beijing, China

    Xing Guo & Wanli Liu

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  1. Junyi Zhao
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  2. Xing Guo
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JZ, XG, WL and CL conceptualized and wrote the manuscript.

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Correspondence to Wanli Liu or Conglei Li.

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Zhao, J., Guo, X., Liu, W. et al. Cytotoxic T cells meet complement: granzyme K as a new initiator of inflammation. Cell Mol Immunol 22, 693–695 (2025). https://doi.org/10.1038/s41423-025-01303-9

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