Notch3 and canonical NF-κB signaling pathways cooperatively regulate Foxp3 transcription

Alessandro Barbarulo, Paola Grazioli, Antonio F. Campese, Diana Bellavia, Giuseppina Di Mario, Maria Pelullo, Ambra Ciuffetta, Sara Colantoni, Alessandra Vacca, Luigi Frati, Alberto Gulino, Maria Pia Felli, Isabella Screpanti

Research output: Contribution to journalArticlepeer-review


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 pTα/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-κB overlapping binding site within the Foxp3 promoter, and we demonstrate that the activation of NF-κB, mainly represented by p65-dependent canonical pathway, plays a positive role in Notch3-dependent regulation of Foxp3 transcription. Accordingly, the deletion of protein kinase Cθ, which mediates canonical NF-κB 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 Cθ, and p65/NF-κB subunit modulates Foxp3 expression, adding new insights in the understanding of the molecular mechanisms involved in regulatory T cell homeostasis and function.

Original languageEnglish
Pages (from-to)6199-6206
Number of pages8
JournalJournal of Immunology
Issue number11
Publication statusPublished - Jun 1 2011

ASJC Scopus subject areas

  • Immunology


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