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

Abstract

Among its varied functions, Notch signaling is involved in peripheral T cells responses. The activation and polarization of CD4+ T cells toward a Th1 lineage are essential steps in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Inhibition of all four Notch receptors with a γ-secretase inhibitor was shown to block Th1-type polarization and to attenuate the symptoms of experimental autoimmune encephalomyelitis. In this study, we have examined the role of individual Notch receptors in proliferation, cytokine production, and encephalitogenic potential of PLP-reactive T cells. Specific induction of Notch1 and Notch3 transcripts were noted in PLP-reactive T cells upon Ag stimulation. However, using γ-secretase inhibitor and Abs blocking distinct Notch receptors, we have found that selective inhibition of Notch3, but not Notch1, receptor abrogated proliferation, Th1- and Th17-type responses of PLP-reactive T cells. Moreover, Notch3 inhibition in T cells correlated with the down-regulated expression of protein kinase Cθ, a kinase with important regulatory function within mature T cells. Thus, selective inhibition of the Notch3 receptor may have important effects on peripheral T cell responses and may offer a new attractive target in treating autoimmune diseases, including multiple sclerosis.

Inactivation of Notch signaling reverses the Th17/Treg imbalance in cells from patients with immune thrombocytopenia

“…Recent studies have drawn direct correlations between specific Notch receptors and IL-17 production in autoimmunity. 38 We here demonstrated that inhibition of Notch signaling by DAPT significantly decreased the secretion of IL-17 in dose-dependent manner in ITP patients. The inactivation of Notch signaling may disrupt IL-17 production, and IL-17 production might be dependent on the Notch signaling in ITP.…”

Regulation of innate and adaptive immunity by Notch

“…In a model of passively transferred EAE, the adoptive transfer of lymph node cells treated with Notch 3-specific neutralizing antibodies, but not with Notch 1-specific neutralizing antibodies, reduced the release of IFNγ and IL-17 by myelin-reactive cells, with a corresponding decrease in the EAE disease scores 75 . Of note, it was not possible to determine in this study whether the lower levels of IFNγ produced resulted from impaired T H 1 cell differentiation and/or from impaired T H 1 cell function.…”

“…This inflammation-mediated demyelination disease of the central nervous system (CNS) can be induced by immunization with myelin antigens, viral infection or transfer of autoreactive T cells. Genetic and pharmacological interference with Notch signalling, as well as administration of blocking antibodies against Notch receptors or Delta-like ligand 4 (DLL4), impeded progression of the disease, resulting in reduced clinical severity 74,75,84,91,92,[118][119] . The mechanisms by which blockage of Notch signalling ameliorates EAE are not fully understood and require further investigation.…”

“…Treatment of mice with γ-secretase inhibitors impeded disease progression in T H 1 cell-mediated experimental autoimmune encephalomyelytis (EAE) 74,75 . It was hypothesized that Notch 1 could bind to an RBPJ-binding sequence on the T-box 21 (Tbx21) gene promoter, which encodes T-bet, the master regulator of T H 1 cell differentiation 74 ; however, such binding of Notch to the Tbx21 gene was not confirmed in another study 76 .…”

Asymmetric Division in the Immuno-Hematopoietic System

“…Antibodies against Notch receptors can be used to regulate Notch signaling. Some antibodies have been already developed against Notch1 and Notch3 receptors (Asano N., et al 2008, Elyaman W., et al 2007, Jurynczyk M., et al 2008, Maekawa Y., et al 2003, Schaller MA., et al 2007and Li K., et al 2008. Antibodies can block specific Notch receptors with a high selectivity, leaving other Notch receptors activated.…”