Journal
JOURNAL OF IMMUNOLOGY
Volume 186, Issue 11, Pages 6199-6206Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1002136
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Funding
- Italian Association for Cancer Research [5432]
- Progetto di Ricerca di Rilevante Interesse Nazionale [2008YSSL7B]
- Fondazione Roma
- European Union [LSHB-CT-2003-543410, FP7-MC-ITN 215761]
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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.
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