Differential Sensitivity to Itk Kinase Signals for T Helper 2 Cytokine Production and Chemokine-Mediated Migration

Abstract

Allergic asthma is dependent on chemokine-mediated Th2 cell migration and Th2 cytokine secretion into the lungs. The inducible T cell tyrosine kinase Itk regulates the production of Th2 cytokines as well as migration in response to chemokine gradients. Mice lacking Itk are resistant to developing allergic asthma. However, the role of kinase activity of Itk in the development of this disease is unclear. In addition, whether distinct Itk-derived signals lead to T cell migration and secretion of Th2 cytokines is also unknown. Using transgenic mice specifically lacking Itk kinase activity, we show that active kinase signaling is required for control of Th2 responses and development of allergic asthma. Moreover, dominant suppression of kinase Itk activity led to normal Th2 responses, but significantly reduced chemokine-mediated migration, resulting in prevention of allergic asthma. These observations indicate that signals required for Th2 responses and migration are differentially sensitive to Itk activity. Manipulation of Itk’s activity can thus provide a new strategy to treat allergic asthma by differentially affecting migration of T cells into the lungs, leaving Th2 responses intact.

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

“…97 Many studies have 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 26 demonstrated that ITK is essential for the control of T helper 2 (Th2) responses and pathological conditions such as lung inflammation, eosinophil infiltration, and mucous production. 98 Consequently, ITK is a therapeutic target for the development of drugs to treat allergic asthma and inflammatory disorders.…”

Interleukin-2-Inducible T-Cell Kinase Deficiency Impairs Early Pulmonary Protection Against Mycobacterium tuberculosis Infection

“…Despite relatively normal number (trending the lower range) of CD8 + αβ T cells, Itk −/− mice exhibited CD4 + αβ T-cell lymphopenia, with reduced proportion of naive and increased memory αβ T cells (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). In the absence of Itk, mouse CD4 + T cells are impaired in Th2 (producing IL-4/5/13) (32)(33)(34)(35)(36)(37)(38), Th9 (producing IL-9) (39), Th17 (producing IL-17) (35,(40)(41)(42), and Tr1 (producing IL-10) cell responses (43), while they are enhanced in Th1 (producing IFN-γ) cell response (32,34,38,44,45). Analysis of Itk −/− mice also reveals altered γδ T-cell development (46)(47)(48)(49); however, the presence and function of γδ T cells has not been evaluated in ITKdeficient humans.…”

Inhibition of the IL-2-inducible tyrosine kinase (Itk) activity: a new concept for the therapy of inflammatory skin diseases

“…(47) showed by employing Itk ‘kinase‐dead’ mutants that the kinase activity of Itk is important for the activation of T cells. The latter observation is supported by experiments showing that Itk kinase activity is central to the development of inflammation in murine models of allergic asthma (48). Although we cannot rule out that Itk in part contributes to T‐cell activation via a scaffolding function, the use of the quite selective small molecule inhibitor, Compound 44, reveals that modulating the kinase activity of Itk has clear anti‐inflammatory effects.…”