Requirement for Itk kinase activity for Th1 Th2 Th17 and iNKT cell cytokine production revealed by an allele sensitive mutant

摘要

Itk^−/− mice exhibit defects in activation, development and function of CD4⁺ and CD8⁺ T cells and iNKT cells. These and other defects in these mice make it difficult to uncouple the developmental versus functional requirement of Itk signaling. Here we report an allele sensitive mutant of Itk (Itkas) whose catalytic activity can be selectively inhibited by analogs of the PP1 kinase inhibitor. We show that Itkas behaves like WT Itk in the absence of the inhibitor and can rescue the development of Itk^−/− T cells in mice. Using this mutant, we show that Itk activity is required not only for Th2, Th17 and iNKT cell cytokine production, but also surprisingly, for Th1 cytokine production. This work has important implications for understanding the role of Itk signaling in development vs. function of iNKT cells, Th1, Th2 and Th17.