T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3

다국어 초록 (Multilingual Abstract)

Specification of mammalian cell lineage requires both gene activation and silencing. The decision of a T helper progenitor lymphocyte to differentiate into either a Th1 or Th2 effector cell depends on the action of two opposing transcription factors, T-bet and GATA-3, which reciprocally activate and silence Th1 and Th2 genetic programs. While the activation of Th-selective cytokine genes by T-bet and GATA-3 has been well studied, the mechanisms by which these factors repress the development of the opposing lineage remain obscure. We report that T-bet represses Th2 lineage commitment by an ITK regulated interaction with GATA-3. Upon T cell receptor signaling, T-bet is phosphorylated at residue Y525 by the TCR-activated Tec kinase, ITK, a posttranslational modification required for optimal T-bet mediated repression of Th2 cytokines. The mechanism of such repression is an ITK-mediated interaction between phosphorylated T-bet and GATA-3, resulting in interference with GAT A-3 binding to DNA. These results provide a novel function for tyrosine phosphorylation of a transcription factor in specifying alternate fates of a common progenitor cell.