Abstract
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 language | English |
|---|---|
| Pages (from-to) | 6199-6206 |
| Number of pages | 8 |
| Journal | Journal of Immunology |
| Volume | 186 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Jun 1 2011 |
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ASJC Scopus subject areas
- Immunology
Cite this
Notch3 and canonical NF-κB signaling pathways cooperatively regulate Foxp3 transcription. / Barbarulo, Alessandro; Grazioli, Paola; Campese, Antonio F.; Bellavia, Diana; Di Mario, Giuseppina; Pelullo, Maria; Ciuffetta, Ambra; Colantoni, Sara; Vacca, Alessandra; Frati, Luigi; Gulino, Alberto; Felli, Maria Pia; Screpanti, Isabella.
In: Journal of Immunology, Vol. 186, No. 11, 01.06.2011, p. 6199-6206.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Notch3 and canonical NF-κB signaling pathways cooperatively regulate Foxp3 transcription
AU - Barbarulo, Alessandro
AU - Grazioli, Paola
AU - Campese, Antonio F.
AU - Bellavia, Diana
AU - Di Mario, Giuseppina
AU - Pelullo, Maria
AU - Ciuffetta, Ambra
AU - Colantoni, Sara
AU - Vacca, Alessandra
AU - Frati, Luigi
AU - Gulino, Alberto
AU - Felli, Maria Pia
AU - Screpanti, Isabella
PY - 2011/6/1
Y1 - 2011/6/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=79958058411&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1002136
DO - 10.4049/jimmunol.1002136
M3 - Article
C2 - 21508258
AN - SCOPUS:79958058411
VL - 186
SP - 6199
EP - 6206
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 11
ER -