T-bet represses TH 17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt

Abstract

Overactive responses by interleukin 17 (IL-17)-producing helper T cells (TH 17 cells) are tightly linked to the development of autoimmunity, yet the factors that negatively regulate the differentiation of this lineage remain unknown. Here we report that the transcription factor T-bet suppressed development of the TH 17 cell lineage by inhibiting transcription of Rorc (which encodes the transcription factor RORt). T-bet interacted with the transcription factor Runx1, and this interaction blocked Runx1-mediated transactivation of Rorc. T-bet Tyr304 was required for formation of the T-bet-Runx1 complex, for blockade of Runx1 activity and for inhibition of the TH 17 differentiation program. Our data reinforce the idea of master regulators that shape immune responses by simultaneously activating one genetic program while silencing the activity of competing regulators in a common progenitor cell. © 2010 Nature America, Inc. All rights reserved.