IL-2-inducible T-cell kinase modulates TH2-mediated allergic airway inflammation by suppressing IFN-γ in naive CD4+ T cells

Arun K. Kannan, Nisebita Sahu, Sunish Mohanan, Sonia Mohinta, Avery August

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Background: Asthma is a predominantly TH2 cell-dominated inflammatory disease characterized by airway inflammation and a major public health concern affecting millions of persons. The Tec family tyrosine kinase IL-2-inducible T-cell kinase (Itk) is primarily expressed in T cells and critical for the function and differentiation of TH cells. Itk -/- mice have a defective TH2 response and are not susceptible to allergic asthma. Objective: We sought to better understand the role of Itk signaling in TH differentiation programs and in the development and molecular pathology of allergic asthma. Methods: Using a murine model of allergic airway inflammation, we dissected the role of Itk in regulating TH cell differentiation through genetic ablation of critical genes, chromatin immunoprecipitation assays, and house dust mite-driven allergic airway inflammation. Results: Peripheral naive Itk-/- CD4+ T cells have substantially increased transcripts and expression of the prototypic TH1 genes Eomesodermin, IFN-γ, T-box transcription factor (T-bet), and IL-12Rβ1. Removal of IFN-γ on the Itk-/- background rescues expression of TH2-related genes in TH cells and allergic airway inflammation in Itk-/- mice. Furthermore, small hairpin RNA-mediated knockdown of Itk in human peripheral blood T cells results in increased expression of mRNA for IFN-γ and T-bet and reduction in expression of IL-4. Conclusion: Our results indicate that Itk signals suppress the expression of IFN-γ in naive CD4 + T cells, which in a positive feed-forward loop regulates the expression of TH1 factors, such as T-bet and Eomesodermin, and suppress development of TH2 cells and allergic airway inflammation.

Original languageEnglish (US)
Pages (from-to)811-820.e2
JournalJournal of Allergy and Clinical Immunology
Volume132
Issue number4
DOIs
StatePublished - Oct 2013

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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