Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells

Abstract

The transcription factor Foxp3 is essential for optimal regulatory T (T reg) cell development and function. Here, we show that CD4+ T cells from Cbl-b RING finger mutant knockin or Cbl-b–deficient mice show impaired TGF-β–induced Foxp3 expression. These T cells display augmented Foxo3a phosphorylation, but normal TGF-β signaling. Expression of Foxo3a rescues Foxp3 expression in Cbl-b–deficient T cells, and Foxo3a deficiency results in defective TGF-β–driven Foxp3 induction. A Foxo3a-binding motif is present in a proximal region of the Foxp3 promoter, and is required for Foxo3a association. Foxo1 exerts similar effects as Foxo3a on Foxp3 expression. This study reveals that Foxo factors promote transcription of the Foxp3 gene in induced T reg cells, and thus provides new mechanistic insight into Foxo-mediated T cell regulation.

Intracellular metabolic pathways control immune tolerance

“…Foxo1-deficient mice show impaired development of Treg cells, and the cells that do develop are non-functional in vivo [95]. Finally, the FoxP3-promoter shows a series of Foxo-binding sites and mutagenesis studies have demonstrated a proximal Foxo-binding element that controls the FoxP3 promoter activity [96,97].…”

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

“…Female Foxo3 knockout mice were found to be sterile due to global primordial follicle activation with subsequent oocyte exhaustion (Castrillon et al ., 2003; Hosaka et al ., 2004). In addition, depletion of Foxo3 resulted in deficient development of regulatory T cells with consequent organ inflammation by a mechanism also involving Foxo1 (Harada et al ., 2010; Kerdiles et al ., 2010). Foxo4 and Foxo6 knockout mice present with only mild phenotypes (Zhu et al ., 2011; Salih et al ., 2012).…”

Gene profile analysis of CD8+ ILT3-Fc induced T suppressor cells

“…Foxo1 controls Foxp3 promoter activity, regulating the differentiation of natural Tregs [23,24]. FOXO1 and FOXO3, which are FOXP3-inducing transcription factors, are also upregulated in ILT3-Fc-treated CD8 T cells, although the amplitude of induction was slightly less than twofold.…”