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Expression of Activated Notch3 in Transgenic Mice Enhances Generation of T Regulatory Cells and Protects against Experimental Autoimmune Diabetes

Thymic-derived dysregulated tolerance has been suggested to occur in type 1 diabetes via impaired generation of CD4(+)CD25(+) T regulatory cells, leading to autoimmune beta cell destruction. In this study, we demonstrate that Notch3 expression is a characteristic feature of CD4(+)CD25(+) cells. Furt...

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Published in:The Journal of immunology (1950) 2003-11, Vol.171 (9), p.4504-4511
Main Authors: Anastasi, Emanuela, Campese, Antonio F, Bellavia, Diana, Bulotta, Angela, Balestri, Anna, Pascucci, Monica, Checquolo, Saula, Gradini, Roberto, Lendahl, Urban, Frati, Luigi, Gulino, Alberto, Di Mario, Umberto, Screpanti, Isabella
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Language:English
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Summary:Thymic-derived dysregulated tolerance has been suggested to occur in type 1 diabetes via impaired generation of CD4(+)CD25(+) T regulatory cells, leading to autoimmune beta cell destruction. In this study, we demonstrate that Notch3 expression is a characteristic feature of CD4(+)CD25(+) cells. Furthermore, streptozotocin-induced autoimmune diabetes fails to develop in transgenic mice carrying the constitutively active intracellular domain of Notch3 in thymocytes and T cells. The failure to develop the disease is associated with an increase of CD4(+)CD25(+) T regulatory cells, accumulating in lymphoid organs, in pancreas infiltrates and paralleled by increased expression of IL-4 and IL-10. Accordingly, CD4(+) T cells from Notch3-transgenic mice inhibit the development of hyperglycemia and insulitis when injected into streptozotocin-treated wild-type mice and display in vitro suppressive activity. These observations, therefore, suggest that Notch3-mediated events regulate the expansion and function of T regulatory cells, leading to protection from experimental autoimmune diabetes and identify the Notch pathway as a potential target for therapeutic intervention in type 1 diabetes.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.171.9.4504