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. 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.
Anastasi
Emanuela
E
Department of Clinical Sciences, University La Sapienza, Rome, Italy.
Campese
Antonio F
AF
Bellavia
Diana
D
Bulotta
Angela
A
Balestri
Anna
A
Pascucci
Monica
M
Checquolo
Saula
S
Gradini
Roberto
R
Lendahl
Urban
U
Frati
Luigi
L
Gulino
Alberto
A
Di Mario
Umberto
U
Screpanti
Isabella
I
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000276:immunology*; D007274:Injections, Intraperitoneal; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D051880:Receptors, Notch; D013311:Streptozocin / Q000008:administration & dosage; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
C499373:Notch3 protein, mouse; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface; D015375:Receptors, Interleukin-2; D051880:Receptors, Notch; D016753:Interleukin-10; C073572:Notch4 protein, mouse; D015847:Interleukin-4; D013311:Streptozocin