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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / pathology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Movement / genetics
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Cell Movement / immunology
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Diabetes Mellitus, Experimental / genetics
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Diabetes Mellitus, Experimental / immunology
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Diabetes Mellitus, Experimental / prevention & control*
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Diabetes Mellitus, Type 1 / genetics
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Diabetes Mellitus, Type 1 / immunology
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Diabetes Mellitus, Type 1 / prevention & control*
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Drug Administration Schedule
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Gene Expression Regulation / immunology*
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Injections, Intraperitoneal
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Interleukin-10 / biosynthesis
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Interleukin-10 / genetics
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Interleukin-4 / biosynthesis
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Interleukin-4 / genetics
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Islets of Langerhans / immunology
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Islets of Langerhans / pathology
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Lymphoid Tissue / immunology
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Lymphoid Tissue / metabolism
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Lymphoid Tissue / pathology
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Male
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Mice
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Mice, Transgenic
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism*
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RNA, Messenger / biosynthesis
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Receptor, Notch3
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Receptor, Notch4
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Receptors, Cell Surface*
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Receptors, Interleukin-2 / biosynthesis
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Receptors, Notch
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Streptozocin / administration & dosage
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / pathology
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Up-Regulation / genetics
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Up-Regulation / immunology*
Substances
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Notch3 protein, mouse
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Proto-Oncogene Proteins
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RNA, Messenger
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Receptor, Notch3
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Receptor, Notch4
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Receptors, Cell Surface
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Receptors, Interleukin-2
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Receptors, Notch
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Interleukin-10
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Notch4 protein, mouse
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Interleukin-4
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Streptozocin