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

Vanja Lazarevic, Xi Chen, Jae Hyuck Shim, Eun Sook Hwang, Eunjung Jang, Alexandra N. Bolm, Mohamed Oukka, Vijay K. Kuchroo, Laurie H. Glimcher

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301 Scopus citations


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.

Original languageEnglish
Pages (from-to)96-104
Number of pages9
JournalNature Immunology
Issue number1
StatePublished - Jan 2011

Bibliographical note

Funding Information:
We thank D. Kozoriz for help in cell sorting; W. Strober (National Institute of Allergy and Infectious Diseases) for retroviral plasmids encoding Runx1 and dominant negative Runx1; S.L. Reiner (University of Pennsylvania) for mice with loxP-flanked Tbx21 alleles; C.B. Wilson (The Bill and Melinda Gates Foundation) for mice with expression of Cre recombinase driven by the Cd4 promoter; and A.-H. Lee, T. Staton-Winslow, M. Greenblatt and M. Wein for critical review of the manuscript. Supported by the US National Institutes of Health (P01 NS038037), the Ragon Institute of MIT, MGH and Harvard (L.H.G.), the National Cancer Research Center (R15-2006-020 to E.S.H.) and the Cancer Research Institute (V.L.).


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