Notch3 and Canonical NF-κB Signaling Pathways Cooperatively Regulate Foxp3 Transcription

Notch3 overexpression has been previously shown to positively regulate the generation and function of naturally occurring regulatory T cells and the expression of Foxp3, in cooperation with the pT alpha/pre-TCR pathway. In this study, we show that Notch3 triggers the trans activation of Foxp3 promoter depending on the T cell developmental stage. Moreover, we discovered a novel CSL/NF-kappa B overlapping binding site within the Foxp3 promoter, and we demonstrate that the activation of NF-kappa B, mainly represented by p65-dependent canonical pathway, plays a positive role in Notch3-dependent regulation of Foxp3 transcription. Accordingly, the deletion of protein kinase C theta, which mediates canonical NF-kappa B activation, markedly reduces regulatory T cell number and per cell Foxp3 expression in transgenic mice with a constitutive activation of Notch3 signaling. Collectively, our data indicate that the cooperation among Notch3, protein kinase C theta, and p65/NF-kappa B subunit modulates Foxp3 expression, adding new insights in the understanding of the molecular mechanisms involved in regulatory T cell homeostasis and function. The Journal of Immunology, 2011, 186: 6199-6206.