Expression of activated Notch3 in transgenic mice enhances generation of T regulatory cells and protects against experimental autoimmune diabetes |
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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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Institution: | Department of Clinical Sciences, University La Sapienza, Rome, Italy. |
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Abstract: | 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. |
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