Interactions among the transcription factors Runx1, RORγt and Foxp3 regulate the differentiation of interleukin 17–producing T cells

Abstract

The molecular mechanisms underlying the differentiation of interleukin 17–producing T helper cells (TH-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 RORγt and Runx1. Runx1 influenced TH-17 differentiation by inducing RORγt expression and by binding to and acting together with RORγt during Il17 transcription. However, Runx1 also interacts with the transcription factor Foxp3, and this interaction was necessary for the negative effect of Foxp3 on TH-17 differentiation. Thus, our data support a model in which the differential association of Runx1 with Foxp3 and with RORγt regulates TH-17 differentiation.

The role of retinoic acid‐related orphan receptor variant 2 and IL‐17 in the development and function of human CD4+ T cells

“…Deficiency in ror-gt results in a major reduction in the number of Th17 cells and protection from experimental autoimmune encephalomyelitis; by corollary, over-expression of Ror-gt promotes Th17 development. Recently, it was shown that Ror-ad or Runx 1 can synergize with Ror-gt to promote IL-17 expression [27,28].…”

“…Deficiency in ror-gt results in a major reduction in the number of Th17 cells and protection from experimental autoimmune encephalomyelitis; by corollary, over-expression of Ror-gt promotes Th17 development. Recently, it was shown that Ror-ad or Runx 1 can synergize with Ror-gt to promote IL-17 expression [27,28].Human Th17 cells express IL-17A, IL-17F, TNF-a, , as well as . Many groups have also examined the expression of chemokine and cytokine receptors on human Th17 cells [26,30,31,[34][35][36][37], with the overall conclusion that co-expression of CCR4, CCR6 and the IL-23R, but not CXCR3, is characteristic and best distinguishes Th17 cells from other human Th-cell subsets.…”

“…In vitro, TGF-b1 and IL-6 polarize naive mouse CD4 1 T cells into Th17 cells [18][19][20], whereas IL-23 is thought to be important for their expansion, survival, effector function and pathogenicity in vivo [20,21,22]. At the molecular level, at least five transcription factors are involved in normal Th17-cell development: Stat3 [17,23,24], a T-cell-specific splice isoform of retinoic acid receptor-related orphan receptor (Ror) known as Ror-gt or Rorc2 [25,26], a splice isoform of Ror-a (Ror-ad) [27], Runx1 [28], and IFN-regulatory factor 4 [29]. Deficiency in ror-gt results in a major reduction in the number of Th17 cells and protection from experimental autoimmune encephalomyelitis; by corollary, over-expression of Ror-gt promotes Th17 development.…”

Aryl hydrocarbon receptor-mediated induction of the microRNA-132/212 cluster promotes interleukin-17–producing T-helper cell differentiation

“…T H 17 differentiation requires retinoid-related orphan receptor (ROR)-γt, a transcription factor that is induced by TGF-β in combination with IL-6, -21, and -23, all of which activate STAT3 phosphorylation (4). Additionally, various host proteins such as aryl hydrocarbon receptor (AHR) (5-7), Runt-related transcription factor 1 (Runx1) (8), Interferon regulatory factor 4 (IRF4) (9), and Basic leucine zipper transcription factor ATF-like (BATF) (10) positively regulate T H 17 differentiation, whereas B-cell lymphoma 6 (Bcl-6) (11,12), Ets-1 (13), Nuclear receptor subfamily 2 group F member 6 (NR2F6) (14), Peroxisome proliferatoractivated receptor gamma (PPAR-γ) (15), Suppressor of cytokine signaling 3 (SOCS3) (16), and Liver X receptor (LXR) (17) inhibit generation of T H 17 cells. However, very few studies have addressed the regulation of T H 17 differentiation by microRNAs, a topic that should be investigated further.…”

Interleukin-17 and its expanding biological functions

“…77,107 Other transcription factors are also involved in the full differentiation of Th17 cells, including IFN regulatory factor 4 and runt-related transcription factor 1. 75,76 Further studies revealed that IL-23 is not required for Th17 differentiation, but can promote the growth, survival and effector function of this lineage.…”