Transcription factor T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the RORγt gene

Overactive T(H)17 responses are tightly linked to the development of autoimmunity, yet the factors that negatively regulate differentiation of this lineage remain unknown. Here, we report that T-bet suppresses the development of the T(H)17 cell lineage by inhibiting the transcription of Rorc. T-bet interacts with the transcription factor Runx1 and this interaction blocks Runx1-mediated transactivation of Rorc. T-bet residue Tyr(304) is required for T-bet-Runx1 complex formation, for blocking Runx1 activity and for inhibiting the T(H)17 differentiation program. These data reinforce the concept 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.