IL-2-inducible T-cell kinase modulates T_H2-mediated allergic airway inflammation by suppressing IFN-γ in naive CD4⁺ T cells

Background: Asthma is a predominantly T_H2 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 T_H cells. Itk ^-/- mice have a defective T_H2 response and are not susceptible to allergic asthma. Objective: We sought to better understand the role of Itk signaling in T_H 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 T_H 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 T_H1 genes Eomesodermin, IFN-γ, T-box transcription factor (T-bet), and IL-12Rβ1. Removal of IFN-γ on the Itk^-/- background rescues expression of T_H2-related genes in T_H 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 T_H1 factors, such as T-bet and Eomesodermin, and suppress development of T_H2 cells and allergic airway inflammation.