title: T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt.
abstract: Overactive responses by interleukin 17 (IL-17)-producing helper T cells (T(H)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 T(H)17 cell lineage by inhibiting transcription of Rorc (which encodes the transcription factor RORγt). 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 T(H)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.
authors.affiliation: Harvard School of Public Health, Department of Immunology and Infectious Diseases, Boston, Massachusetts, USA. vlazarev@hsph.harvard.edu
authors.forename: Vanja
authors.initials: V
authors.lastname: Lazarevic
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Jae-Hyuck
authors.initials: JH
authors.lastname: Shim
authors.forename: Eun-Sook
authors.initials: ES
authors.lastname: Hwang
authors.forename: Eunjung
authors.initials: E
authors.lastname: Jang
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Bolm
authors.forename: Mohamed
authors.initials: M
authors.lastname: Oukka
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000098815:T-bet Transcription Factor
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D016207:Cytokines; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor