title: Notch3 and pTalpha/pre-TCR sustain the in vivo function of naturally occurring regulatory T cells.
abstract: Dysregulated generation and/or function of naturally occurring 'CD4(+)CD25(+) regulatory T cells' (T(reg)s) 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 T(reg)s, 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 pTalpha gene is up-regulated in naturally occurring T(reg)s, at both mRNA and protein levels. Moreover, by using double mutant mice, with T cell-targeted constitutive activation of Notch3 in a pTalpha(-/-) background, we demonstrate that pTalpha deletion significantly counteracts the Notch3-dependent expansion, the increased FoxP3 expression and the enhanced in vitro activity of naturally occurring T(reg)s. Notably, the absence of pTalpha 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 T(reg)s bearing pTalpha deletion. Collectively, our data suggest that pTalpha expression is required for the in vivo function of naturally occurring T(reg)s and that the activation of Notch3 signaling may positively regulate the function of this population, through the pTalpha/pre-T cell receptor pathway.
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy
authors.forename: Antonio F
authors.initials: AF
authors.lastname: Campese
authors.forename: Paola
authors.initials: P
authors.lastname: Grazioli
authors.forename: Sara
authors.initials: S
authors.lastname: Colantoni
authors.forename: Emanuela
authors.initials: E
authors.lastname: Anastasi
authors.forename: Marco
authors.initials: M
authors.lastname: Mecarozzi
authors.forename: Saula
authors.initials: S
authors.lastname: Checquolo
authors.forename: Gabriele
authors.initials: G
authors.lastname: De Luca
authors.forename: Diana
authors.initials: D
authors.lastname: Bellavia
authors.forename: Luigi
authors.initials: L
authors.lastname: Frati
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D007108:Immune Tolerance / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054504:Precursor Cells, T-Lymphoid / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000071656:Receptor, Notch3; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015533:Transcriptional Activation
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D008562:Membrane Glycoproteins; C499373:Notch3 protein, mouse; D000071656:Receptor, Notch3; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051880:Receptors, Notch; C090377:pre-T cell receptor alpha