title: IL-2-inducible T-cell kinase modulates TH2-mediated allergic airway inflammation by suppressing IFN-γ in naive CD4+ T cells.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Microbiology and Immunology, Cornell University, Ithaca, NY.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Kannan
authors.forename: Nisebita
authors.initials: N
authors.lastname: Sahu
authors.forename: Sunish
authors.initials: S
authors.lastname: Mohanan
authors.forename: Sonia
authors.initials: S
authors.lastname: Mohinta
authors.forename: Avery
authors.initials: A
authors.lastname: August
mesh_terms: D000818:Animals; D001249:Asthma / Q000209:etiology / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000209:etiology / Q000276:immunology*; D007249:Inflammation / Q000209:etiology / Q000276:immunology*; D007371:Interferon-gamma / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D039981:Pyroglyphidae / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase
keywords: AHR; APC; Airways hyperresponsiveness; Antigen-presenting cell; BALF; Bronchoalveolar lavage fluid; CNS; ChIP; Chromatin immunoprecipitation; Conserved noncoding sequence; DKO; Double knockout; Eomes; Eomesodermin; HDM; House dust mite; IFN-γ; IL-2–inducible T-cell kinase; Itk; P/I; Phorbol 12-myristate 13-acetate/ionomycin; Quantitative PCR; Small hairpin RNA; T(H)2; T-bet; T-box transcription factor; T-cell receptor; TCR; Tec kinase; WT; Wild type; allergic asthma; qPCR; shRNA