Notch signalling in the regulation of peripheral immunity

Abstract

Notch signalling plays a critical role in embryogenesis, influencing the differentiation and growth of a variety of cell types across the species. In the mammalian immune system, Notch signalling operates at various levels; it controls the differentiation of haematopoietic stem cells and directs the early development of the T and B-cell lineages. It is also involved in the maturation of both CD4+ and CD8+ T cells in the thymus. The biological activities of this pathway extend beyond lymphocyte ontogeny; recent evidence has shown that it also contributes to the regulation of the peripheral immune system through its ability to influence cell survival and growth. In fulfilling this function, Notch signalling appears to act in conjunction with defined immunological signals such as cytokines, T-cell antigen receptor and co-stimulatory receptor-mediated signalling. In this review we discuss the potential of the Notch signalling pathway in the maintenance of homeostasis within the immune system affecting both peripheral tolerance and the negative feedback controlling productive immunity. The therapeutic manipulation of this pathway is likely to have broad application in a range of immunologically based diseases.

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

“…Indeed, it has been previously shown that activation of Notch signaling, by overexpressing the specific Notch ligand Jagged/Serrate1 in APCs, in peripheral murine T cells results in the differentiation of Ag-specific CD4 ϩ lymphocytes into T-reg cells, which can transfer tolerance to naive mice (30). Conversely, Ag-dependent T cell activation has been shown to trigger the activation of the Notch signaling pathway, since stimulation of purified murine CD4 ϩ T cells with anti-CD3 and anti-CD28 Abs has been shown to induce a transient increase in Notch ligand and receptor expression and the concomitant addition of IL-10 further increases the transcription of Notch ligand genes (31). More recently, Notch signaling, including the expression of the Hes1 target gene, has also been shown to be enhanced in human peripheral CD4 ϩ CD25 ϩ cells upon in vitro stimulation with anti-CD3 and anti-CD28 Abs, while Deltex, a positive regulator of the Notch signaling pathway, is highly up-regulated in resting CD4 ϩ CD25 ϩ cells compared with CD4 ϩ CD25 Ϫ cells (32).…”

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

“…Third, when mice with experimental autoimmune encephalomyelitis (a model of immune mediated demyelination) were treated with a γ-secretase inhibitor, MW167, which prevents Notch signaling, myelin repair and axonal survival were improved [66]. However, Notch is also expressed by cells associated with inflammation [67], thus it remains possible, even likely that the mechanism by which MW167 enhances CNS myelin repair occurs through immunomodulation rather than by directly stimulating OPC differentiation. It would be of interest to assess the effect of MW167 directly on OPC differentiation and myelination by using purified OPC cultures or myelinating co-cultures.…”

Antigen-induced regulatory T cells

“…Stimulation of the T-cell surface molecule ICOS (inducible costimulatory molecule) 56,57 and Notch during antigen presentation has also been shown to induce antigen-specific Trs. [58][59][60][61][62][63][64] The ICOS molecule has been implicated in the regulation of the Th2 memory response. After activation by its ligand, ICOS binds phosphoinositide-dependent kinase 3 (PI3K) and activates phosphoinositide-dependent kinase 1 (PIK1) and protein kinase B (PKB).…”