TEC-family kinases: regulators of T-helper-cell differentiation

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Abstract
The phenotypes of mice that are deficient in TEC-family kinases have previously been associated with defects in phospholipase C-γ1 activation and Ca2+ mobilization. Now, several studies indicate that the TEC-family kinase ITK (interleukin-2-inducible T-cell kinase) is also required for the actin reorganization and cell polarization that occurs after T-cell-receptor engagement. There are striking similarities between T cells that are deficient in ITK and VAV1 with respect to biochemical and cellular defects, including impaired reorganization of actin, and effects on recruitment of protein kinase C-θ (PKC-θ) and activation of transcription factors. Evidence implicates TEC-family kinases in the development of T helper (TH) cells. Overexpression of RLK (resting lymphocyte kinase) by Jurkat T cells or in mice leads to skewed differentiation towards the TH1-cell lineage. T cells from Itk−/− mice produce decreased levels of TH2 cytokines and fail to mount responses to several TH2-cell-inducing pathogens. Mice that are deficient in VAV1 or PKC-θ also show TH2-cell defects, implying that there are common pathways regulating TH2-cell development. The recent finding that specific inhibitors of ITK ameliorate disease in a mouse model of allergic asthma indicates that ITK is a potential therapeutic target for TH2-cell-mediated diseases. The defective TH2-cell response to infection with Schistosoma mansoni that is observed in Itk−/− mice is rescued by deletion of RLK, despite the presence of more severe biochemical defects in Rlk−/−Itk−/− T cells. This indicates that global inhibitors of TEC-family kinases might not be ideal therapeutic agents. A role for TEC in TH-cell development has not yet been examined, but recent findings indicate that this TEC-family kinase might have unique functions in effector T cells.