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

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.