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

Emanuela Anastasi, Antonio F. Campese, Diana Bellavia, Angela Bulotta, Anna Balestri, Monica Pascucci, Saula Checquolo, Roberto Gradini, Urban Lendahl, Luigi Frati, Alberto Gulino, Umberto Di Mario, Isabella Screpanti

Research output: Contribution to journalArticlepeer-review

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 β 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.

Original languageEnglish
Pages (from-to)4504-4511
Number of pages8
JournalJournal of Immunology
Volume171
Issue number9
Publication statusPublished - Oct 1 2003

ASJC Scopus subject areas

  • Immunology

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