Gene Expression in the Gitr Locus Is Regulated by NF-κB and Foxp3 through an Enhancer

Abstract

Gitr and Ox40, two members of the TNFR superfamily, play important roles in regulating activities of effector (Teff) and regulatory (Treg) T cells. Their gene expression is induced by T cell activation, and further upregulated in Foxp3+ Treg. Although the role of Foxp3 as a transcriptional repressor in Treg is well established, the mechanisms underlying Foxp3-mediated transcriptional upregulation remain poorly understood. This transcription factor seems to upregulate expression not only of Gitr and Ox40, but also other genes including Ctla4, Il35, Cd25, all critical to Treg function. In order to investigate how Foxp3 achieves such upregulation, we analyzed its activity on Gitr and Ox40 genes located within a 15.1-kb region. We identified an enhancer located down stream of the Gitr gene, and both Gitr and Ox40 promoter activities were shown to be upregulated by the NF-κB-mediated enhancer activity. We also show, using the Gitr promoter, that the enhancer activity was further upregulated in conjunction with Foxp3. Foxp3 appears to stabilize NF-κB p50 binding by anchoring it to the enhancer, so enabling local accumulation of transcriptional complexes containing other member of the NF-κB and IκB families. These findings may explain how Foxp3 can activate expression of certain genes while suppressing others.

DNMT1 cooperates with MBD4 to inhibit the expression of Glucocorticoid‐induced TNFR‐related protein in human T cells

“…GITR does not express in Jurkat T cells . FOXP3 was previously reported to activate GITR transcription in Treg cells . However, the overexpression of FOXP3 in Jurkat T cells did not induce GITR expression (Fig.…”

An NF-κB Transcription-Factor-Dependent Lineage-Specific Transcriptional Program Promotes Regulatory T Cell Identity and Function

“…Given that FoxP3 is the lineage specific transcription factor that differentiates Treg and Tconv cells, it is possible that FoxP3 itself coordinates Treg-specific p65-binding and activity. It was previously suggested that FoxP3 and p65 may influence NF-κB activity, for instance on the GITR locus (Tone et al, 2014). Analysis of our ChIPseq and public data showed binding for both p65 and Foxp3 on multiple Treg genes, including Foxp3 itself, Ikzf2, Lrrc32 or Ctla4 .…”

Cambogin suppresses dextran sulphate sodium‐induced colitis by enhancing Treg cell stability and function

“…Cambogin did not alter the expression of TLR4 and Myd88, but cambogin suppressed the MAPK and IKK/IκB pathways, which play leading roles in the inflammatory process. Indeed, it is complicated and difficult to determine the specific mechanism of cambogin on Foxp3 expression, as the role of transcription factors, such as AP-1, NF-κB, NF-AT and stat5, in Foxp3 expression during Treg cell development and functional regulation is still debatable (Bettelli et al, 2005;Lee et al, 2008;Tone et al, 2014;Harusato et al, 2017). Nevertheless, the results of the present study demonstrated that cambogin promotes the expression of Foxp3 expression in an inflammatory environment.…”