Defining the transcriptional regulation of NR2F6 in CD4+ T helper cell responses

Abstract

Abstract NR2F6, an orphan member of the nuclear receptor superfamily of ligand-regulated transcription factors, plays an important role in CD4+ T cell differentiation and effector function. As a transcriptional repressor, NR2F6 can directly repress expression of the pro-inflammatory cytokines IL-2, IL-17A, IL-21, and IFNγ. Our overexpression data is consistent with this, demonstrating NR2F6 represses IL-17A production in TH17 cells, indicating it also may play a role in autoimmune regulation. Furthermore, genetic experiments have demonstrated the ability of NR2F6 to reduce tumor burden and develop host-protective immunological memory, a consequence of it acting as an immune checkpoint in effector T cells. Collectively, these data suggest that modulation of NR2F6 activity may have important clinical applications for autoimmune and cancer immune therapy. To date, no synthetic or endogenous ligands have been identified that modulate its activity and little is known about its transcriptional function at the molecular level. Here through integrating NR2F6 overexpression and cytokine profiling studies with -omics based approaches, such as RNAseq using T cell specific NR2F6 knockouts, we are working to elucidate NR2F6’s transcriptional function in T cells. Additionally, efforts to identify NR2F6 selective small molecules is underway so we can address how ligand modulation of NR2F6 alters its function. These experiments will help define the molecular mechanisms of NR2F6, which are poorly understood, and determine its niche in cancer immunotherapy and autoimmunity. Supported by R01 CA225890