T-bet and GATA3 orchestrate Th1 and Th2differentiation through lineage-specific targetingof distal regulatory elements

摘要

T-bet and GATA3 regulate the CD4 t T cell Th1/Th2 cell fate decision but little is knownabout the interplay between these factors outside of the murine Ifng and Il4/Il5/Il13 loci. Herewe show that T-bet and GATA3 bind to multiple distal sites at immune regulatory genes inhuman effector T cells. These sites display markers of functional elements, act as enhancersin reporter assays and are associated with a requirement for T-bet and GATA3. Furthermore,we demonstrate that both factors bind distal sites at Tbx21 and that T-bet directly activates itsown expression. We also show that in Th1 cells, GATA3 is distributed away from Th2 genes,instead occupying T-bet binding sites at Th1 genes, and that T-bet is sufficient to induceGATA3 binding at these sites. We propose these aspects of T-bet and GATA3 function areimportant for Th1/Th2 differentiation and for understanding transcription factor interactionsin other T cell lineage decisions.