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

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.

Notch3 Inhibition in Myelin-Reactive T Cells Down-Regulates Protein Kinase Cθ and Attenuates Experimental Autoimmune Encephalomyelitis

“…For example, mice with transgenic expression of activated Notch3 generate increased numbers of regulatory CD4 ϩ CD25 ϩ T cells and fail to develop experimental autoimmune diabetes (14). Therefore, we have asked whether the effect of Notch3 inhibition on EAE, which ameliorated and reduced autoreactive T cell transfer, may have been due to the expansion of regulatory T cells.…”

“…It has been shown previously that transgenic mice with the constitutive activation of Notch3 receptor generate in the thymus a large population of CD4 ϩ CD25 ϩ regulatory T cells which protect them from experimental autoimmune diabetes (14). In our study, we assessed expression of CD25 and FoxP3 in CD4 ϩ T cells cultured alone or in the presence of GSI or Notch1-and Notch3-blocking Abs.…”

Acetylation controls Notch3 stability and function in T-cell leukemia

“…Fluorescence-activated cell sorting analysis Freshly isolated cells from thymi, spleens, blood and lymph nodes were prepared and stained, as previously described (Anastasi et al, 2003), and analyzed on a FACS-Calibur with CellQuest software (BD-Biosciences, San Jose, CA, USA). Cells were stained with APC-, PE-, PerCP-Cy5.5 or FITC-conjugated mAbs against: CD4 (553051), CD8 (553033), CD45R/B220 (561101) and Thy1 (553004) (BD-PharMingen, San Diego, CA, USA).…”

A Genome-Wide Analysis Identifies a Notch–RBP-Jκ–IL-7Rα Axis That Controls IL-17–Producing γδ T Cell Homeostasis in Mice

“…Dll4 on dendritic cells induced the differentiation of Th17 cells through the Th17-specific transcription factor RORgt (4). Furthermore, Notch3 signaling induced by Jagged2 was reported to promote the expansion of regulatory T cells (5,6). Thus, Notch signaling plays critical roles in ab T cell differentiation and function in the periphery.…”