Interleukin-2-inducible T Cell Kinase (Itk) Network Edge Dependence for the Maturation of iNKT Cell

Invariant natural killer T (iNKT) cells are a unique subset of innate T lymphocytes that are selected by CD1d. They have diverse immune regulatory functions via the rapid production of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4). In the absence of signaling nodes Itk and Txk, Tec family non-receptor tyrosine kinases, mice exhibit a significant block in iNKT cell development. We now show here that although the Itk node is required for iNKT cell maturation, the kinase domain edge of Itk is not required for continued maturation iNKT cells in the thymus compared with Itk-null mice. This rescue is dependent on the expression of the Txk node. Furthermore, this kinase domain independent edge rescue correlates with the increased expression of the transcription factors T-bet, the IL-2/IL-15 receptor beta chain CD122, and suppression of eomesodermin expression. By contrast, alpha-galactosyl ceramide induced cytokine secretion is dependent on the kinase domain edge of Itk. These findings indicate that the Itk node uses a kinase domain independent edge, a scaffolding function, in the signaling pathway leading to the maturation of iNKT cells. Furthermore, the findings indicate that phosphorylation of substrates by the Itk node is only partially required for maturation of iNKT cells, while functional activation of iNKT cells is dependent on the kinase domain/activity edge of Itk.