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International Immunology Advance Access originally published online on May 21, 2009
International Immunology 2009 21(6):727-743; doi:10.1093/intimm/dxp042
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© The Japanese Society for Immunology. 2009. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Notch3 and pT{alpha}/pre-TCR sustain the in vivo function of naturally occurring regulatory T cells

Antonio F. Campese1, Paola Grazioli1, Sara Colantoni1, Emanuela Anastasi2, Marco Mecarozzi1, Saula Checquolo1, Gabriele De Luca1, Diana Bellavia1, Luigi Frati1,3, Alberto Gulino1,3 and Isabella Screpanti1

1 Department of Experimental Medicine
2 Department of Clinical Sciences, Sapienza University, 00161 Roma, Italy
3 Neuromed Institute, Pozzilli, Italy

Correspondence to: I. Screpanti; Laboratory of Molecular Pathology, Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161 Roma, Italy; E-mail: isabella.screpanti{at}uniroma1.it

Dysregulated generation and/or function of naturally occurring ‘CD4+CD25+ regulatory T cells’ (Tregs) play key role in the development of autoimmune diseases, including type 1 diabetes. Recent findings suggest that Notch3 signaling activation promotes thymic generation and peripheral expansion and in vivo function of naturally occurring Tregs, thus preventing autoimmune diabetes progression in mouse models. However, the mechanisms underlying these effects have remained elusive, thus far. Here, we show that the expression of pT{alpha} gene is up-regulated in naturally occurring Tregs, at both mRNA and protein levels. Moreover, by using double mutant mice, with T cell-targeted constitutive activation of Notch3 in a pT{alpha}–/– background, we demonstrate that pT{alpha} deletion significantly counteracts the Notch3-dependent expansion, the increased FoxP3 expression and the enhanced in vitro activity of naturally occurring Tregs. Notably, the absence of pT{alpha} also impairs the Notch3-dependent protection against experimentally induced autoimmune diabetes. Finally, by adoptive cell transfer experiments, we demonstrated that this failure is directly related to the impaired in vivo function of naturally occurring Tregs bearing pT{alpha} deletion. Collectively, our data suggest that pT{alpha} expression is required for the in vivo function of naturally occurring Tregs and that the activation of Notch3 signaling may positively regulate the function of this population, through the pT{alpha}/pre-T cell receptor pathway.

Keywords: autoimmunity, diabetes, Notch3, pre-TCR, T cells

Transmitting editor: L. Moretta

Received 2 December 2008, accepted 9 April 2009.


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