The transcription factor NFIL3 controls regulatory T-cell function and stability

Regulatory T (Treg) cells are a CD4 T-cell subset with an important role in immune tolerance; however, the mechanisms underlying Treg cell differentiation and function are incompletely understood. Here, we show that NFIL3/E4BP4, a transcription factor, plays a key role in Treg cell differentiation and function. Microarray analysis showed that Treg cells had lower Nfil3 expression than all other CD4 T-cell subsets. Overexpression of Nfil3 in Treg cells led to diminished expression of Foxp3 and other signature Treg genes, including Il2ra , Icos , Tnfrsf18 , and Ctla4 . Furthermore, Nfil3 -overexpressing Treg cells exhibited impaired immunosuppressive activity in vitro and in vivo. We discovered that NFIL3 directly binds to and negatively regulates the expression of Foxp3 . In addition, bisulfite sequencing revealed that NFIL3 induces methylation at Foxp3 locus regulatory CpG sites, which contributes to the control of Treg cell stability. Together, these data indicate that NFIL3 impairs Treg cell function through the downregulation of Foxp3 expression. Autoimmunity: Revealing the genes behind immune cell responses The identification of a protein involved in the functioning of certain immune cells may inform future therapies for autoimmune diseases and cancer. Regulatory T cells (Treg) are immune cells that play a vital role in preventing autoimmunity, by suppressing immune responses. Abnormal Treg activity is implicated in cancer and autoimmune conditions like colitis. Gap Ryol Lee and co-workers at Sogang University, Seoul, South Korea, found that a transcription factor protein called NFIL3, coded for by the Nfil3 gene, helps regulate Treg function and differentiation. The team found that Nfil3 was expressed at lower levels in Treg cells than in other T cell populations. When Nfil3 was overexpressed in Treg cells, the expression of another critical regulator gene for Treg functions was reduced, impairing the activity of the immune cells.