Indispensable Role of the Runx1-Cbfβ Transcription Complex for In Vivo-Suppressive Function of FoxP3+ Regulatory T Cells

Abstract

Naturally arising regulatory T (Treg) cells express the transcription factor FoxP3, which critically controls the development and function of Treg cells. FoxP3 interacts with another transcription factor Runx1 (also known as AML1). Here, we showed that Treg cell-specific deficiency of Cbfbeta, a cofactor for all Runx proteins, or that of Runx1, but not Runx3, induced lymphoproliferation, autoimmune disease, and hyperproduction of IgE. Cbfb-deleted Treg cells exhibited impaired suppressive function in vitro and in vivo, with altered gene expression profiles including attenuated expression of FoxP3 and high expression of interleukin-4. The Runx complex bound to more than 3000 gene loci in Treg cells, including the Foxp3 regulatory regions and the Il4 silencer. In addition, knockdown of RUNX1 showed that RUNX1 is required for the optimal regulation of FoxP3 expression in human T cells. Taken together, our results indicate that the Runx1-Cbfbeta heterodimer is indispensable for in vivo Treg cell function, in particular, suppressive activity and optimal expression of FoxP3.

Functional Plasticity of Antigen-Specific Regulatory T Cells in Context of Tumor

“…qPCR analysis revealed that expression of some Treg-related genes, including Runx1 (28,29) and galectin 1 (30), is maintained in ex-Tregs (Fig. 4).…”

FOXP3+ regulatory T cells and their functional regulation

“…16,65 The binding of a RUNX1-CBF-b complex (runtrelated transcription factor 1-core-binding factor subunit-b complex) to CNS2 was shown to be crucial for sustaining a high and stable level of FOXP3 expression in Treg cells. 66 TCR stimulation activates the NF-kB family member REL for binding to CNS3, and is required for opening the Foxp3 promoter/enhancer region to promote FOXP3 expression. [67][68][69] Using CNS region-specific deficient mice, all the above findings were corroborated by Zheng and colleagues.…”

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

“…CNS2 contains the TSDR and is responsible for maintenance of FOXP3 in all dividing Treg and CNS3 is the pioneer site for FOXP3 expression in thymic origin nTreg 63. Occupancy by specific transcription factors at each of these loci is now characterised, and this includes AP1 and NFAT at CNS1,59 Runx1 and CBFβ at CNS264 and cREl at CNS3 63. The observation that naïve human CD4+ T cells induce FOXP3 upon activation,65, 66, 67 and that in the presence of TGFβ and all‐trans retinoic acid (ATRA)63 the expression of FOXP3 is stabilised to some degree, was defined transcriptionally by the finding that the activation‐induced expression of FOXP3 results from partial but not complete demethylation of the FOXP3 locus in iTreg 37.…”