Interactions among the transcription factors Runx1, RORgammat and Foxp3 regulate the differentiation of interleukin 17-producing T cells.
The molecular mechanisms underlying the differentiation of interleukin 17-producing T helper cells (T(H)-17 cells) are still poorly understood. Here we show that optimal transcription of the gene encoding interleukin 17 (Il17) required a 2-kilobase promoter and at least one conserved noncoding (enhancer) sequence, CNS-5. Both cis-regulatory elements contained regions that bound the transcription factors RORgammat and Runx1. Runx1 influenced T(H)-17 differentiation by inducing RORgammat expression and by binding to and acting together with RORgammat during Il17 transcription. However, Runx1 also interacts with the transcription factor Foxp3, and this interaction was necessary for the negative effect of Foxp3 on T(H)-17 differentiation. Thus, our data support a model in which the differential association of Runx1 with Foxp3 and with RORgammat regulates T(H)-17 differentiation.
Zhang
Fuping
F
Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Meng
Guangxun
G
Strober
Warren
W
D000818:Animals; D002454:Cell Differentiation; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics*; D019169:Jurkat Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014158:Transcription, Genetic
D050676:Core Binding Factor Alpha 2 Subunit; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse