T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements

Aditi Kanhere, Arnulf Hertweck, Urvashi Bhatia, M. Refik Gökmen, Esperanza Perucha, Ian Jackson, Graham M. Lord () and Richard G. Jenner ()
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Aditi Kanhere: University College London
Arnulf Hertweck: Guy’s and St Thomas’ Hospital and King’s College London
Urvashi Bhatia: Guy’s and St Thomas’ Hospital and King’s College London
M. Refik Gökmen: Guy’s and St Thomas’ Hospital and King’s College London
Esperanza Perucha: Guy’s and St Thomas’ Hospital and King’s College London
Ian Jackson: Guy’s and St Thomas’ Hospital and King’s College London
Graham M. Lord: Guy’s and St Thomas’ Hospital and King’s College London
Richard G. Jenner: University College London

Nature Communications, 2012, vol. 3, issue 1, 1-12

Abstract: Abstract T-bet and GATA3 regulate the CD4+ T cell Th1/Th2 cell fate decision but little is known about the interplay between these factors outside of the murine Ifng and Il4/Il5/Il13 loci. Here we show that T-bet and GATA3 bind to multiple distal sites at immune regulatory genes in human effector T cells. These sites display markers of functional elements, act as enhancers in 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 its own 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 induce GATA3 binding at these sites. We propose these aspects of T-bet and GATA3 function are important for Th1/Th2 differentiation and for understanding transcription factor interactions in other T cell lineage decisions.

Date: 2012
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DOI: 10.1038/ncomms2260

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