The USP7-STAT3- granzyme- Par- 1 axis regulates allergic inflammation by promoting differentiation of IL-5- producing Th2 cells

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Abstract

Uncontrolled type 2 immunity by type 2 helper T (Th2) cells causes intractable allergic diseases; however, whether the interaction of CD4+ T cells shapes the pathophysiology of allergic diseases remains unclear. We identified a subset of Th2 cells that produced the serine proteases granzyme A and B early in differentiation. Granzymes cleave protease-activated receptor (Par)-1 and induce phosphorylation of p38 mitogen-activated protein kinase (MAPK), resulting in the enhanced production of IL-5 and IL-13 in both mouse and human Th2 cells. Ubiquitin-specific protease 7 (USP7) regulates IL-4- induced phosphorylation of STAT3, resulting in granzyme production during Th2 cell differentiation. Genetic deletion of Usp7 or Gzma and pharmacological blockade of granzyme B ameliorated allergic airway inflammation. Furthermore, PAR-1+ and granzyme+ Th2 cells were colocalized in nasal polyps from patients with eosinophilic chronic rhinosinusitis. Thus, the USP7-STAT3- granzymes- Par- 1 pathway is a potential therapeutic target for intractable allergic diseases.

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Kumagai, J., Kiuchi, M., Kokubo, K., Yagyu, H., Nemoto, M., Tsuji, K., … Hirahara, K. (2023). The USP7-STAT3- granzyme- Par- 1 axis regulates allergic inflammation by promoting differentiation of IL-5- producing Th2 cells. Proceedings of the National Academy of Sciences of the United States of America, 120. https://doi.org/10.1073/pnas.2302903120

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