Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells

Abstract

Cell differentiation involves activation and silencing of lineage-specific genes. Here we show that the transcription factor Runx3 is induced in T helper type 1 (T(H)1) cells in a T-bet-dependent manner, and that both transcription factors T-bet and Runx3 are required for maximal production of interferon-gamma (IFN-gamma) and silencing of the gene encoding interleukin 4 (Il4) in T(H)1 cells. T-bet does not repress Il4 in Runx3-deficient T(H)2 cells, but coexpression of Runx3 and T-bet induces potent repression in those cells. Both T-bet and Runx3 bind to the Ifng promoter and the Il4 silencer, and deletion of the silencer decreases the sensitivity of Il4 to repression by either factor. Our data indicate that cytokine gene expression in T(H)1 cells may be controlled by a feed-forward regulatory circuit in which T-bet induces Runx3 and then 'partners' with Runx3 to direct lineage-specific gene activation and silencing.

Runt-related transcription factor 3 is involved in the altered phenotype and function in ThPok-deficient invariant natural killer T cells

“…Results assessing in vitro IL-4 secretion were similar to results of the in vivo assays, namely, markedly reduced IL-4 levels were observed in iNKT cells from ThPok-deficient mice both at 2 and 24 h. However, it was noteworthy that iNKT cells from DKO mice produced more IL-4 than iNKT cells from ThPok-deficient mice, although the levels were lower than those produced by iNKT cells from Runx3-deficient and WT mice. The recovered IL-4 production in DKO mice was expected because several studies have reported an inhibitory effect of Runx3 on IL-4 expression in T cells, 33,49 suggesting a similar mechanism of action of Runx3 in iNKT cells. In accord with the findings of IL-17A secretion in response to aGalCer in vivo, the in vitro experiments indicated that ThPok disruption led to significantly higher expression of IL-17A by thymus-derived iNKT cells upon stimulation compared with iNKT cells from Runx3-deficient and WT control mice, whereas the sorted iNKT cells from DKO mice secreted less IL-17A than the iNKT cells from ThPok-deficient mice (Figure 4c).…”

“…31,32 Furthermore, Runx3 functions to skew naive CD4 1 T cells toward the Th1 lineage, and Runx3 and T-bet interact to enhance the expression of IFN-c and silence IL-4 in Th1-type cells. 33 Moreover, Runx1 and Runx3 are both involved in IL-17 production by T regulatory cells. 34 Studies in mice have confirmed that in the absence of ThPok, CD4 1 NKT cells completely disappear and a new population of CD8 1 NKT cells emerges; thus, we sought to determine whether Runx1 and Runx3 are involved in the development of CD8 1 iNKT cells in ThPok-deficient mice and whether they play a part in the response of iNKT cells to antigen stimulation.…”

New insights into IL-12-mediated tumor suppression

“…[22][23][24] Moreover, IL-12 polarizes T cells into a type 1 helper T (Th1) effector cell phenotype. [25][26][27] Th1 polarization is further pronounced by IL-12 inhibiting the developmental program of type 2 helper T cells 28 and interference with the differentiation of regulatory T cells (Tregs) and Th17 cells induced by TGF-b. 29 Additionally, IL-12 programs effector T cells for optimal generation of effector memory T cells and T follicular helper cells.…”

Cell division curtails helper phenotype plasticity and expedites helper T‐cell differentiation

“…36,37 Additionally, experiments have shown that master transcription factors form homodimers facilitating cooperative binding to DNA. 38,39 The formation of heterodimeric complexes leads to crossinhibition between master transcription factors. [40][41][42] When these biochemical properties are modelled mathematically, the resulting model includes high and low stable expression states 9,10 (see Box 1).…”