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.
Keywords:
asthma, intractable allergic disease; granzyme; pathogenic Th2 cell; signal transducers and activators of transcription (STAT)3; ubiquitin specific protease 7 (USP7).
MeSH terms
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Animals
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Cell Differentiation
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Granzymes / genetics
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Granzymes / metabolism
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Humans
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Hypersensitivity*
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Inflammation / metabolism
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Interleukin-5 / metabolism
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Mice
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism
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Th2 Cells*
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Ubiquitin-Specific Peptidase 7 / metabolism
Substances
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Granzymes
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Interleukin-5
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Ubiquitin-Specific Peptidase 7
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USP7 protein, human
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STAT3 protein, human
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STAT3 Transcription Factor
Grants and funding
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JP19H05650/Ministry of Education, Culture, Sports, Science and Technology (MEXT)
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20H03685/Ministry of Education, Culture, Sports, Science and Technology (MEXT)
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17K08876/Ministry of Education, Culture, Sports, Science and Technology (MEXT)
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18K07164/Ministry of Education, Culture, Sports, Science and Technology (MEXT)
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19K16683/Ministry of Education, Culture, Sports, Science and Technology (MEXT)
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21H05121/Ministry of Education, Culture, Sports, Science and Technology (MEXT)
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19K23858/Ministry of Education, Culture, Sports, Science and Technology (MEXT)
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22K15485/Ministry of Education, Culture, Sports, Science and Technology (MEXT)
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JP21H05120/Ministry of Education, Culture, Sports, Science and Technology (MEXT)
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JP20ek0410060/Japan Agency for Medical Research and Development (AMED)
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JP22ek0410092/Japan Agency for Medical Research and Development (AMED)
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JP20gm1210003/Japan Agency for Medical Research and Development (AMED)
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JPMJFR200R/JST FORREST program