Jagged1 and Delta1 Differentially Regulate the Outcome of Experimental Autoimmune Encephalomyelitis

Abstract

Notch signaling plays an important role during T cell development in the thymus and in T cell activation but the role of Notch in autoimmunity is not clear. We investigated the role of Jagged1 and Delta1 in experimental autoimmune encephalomyelitis. During experimental autoimmune encephalomyelitis, Delta1 expression is up-regulated on dendritic cells and B cells after priming while Jagged1 is up-regulated only on dendritic cells. Administration of anti-Jagged1 Ab exacerbated clinical disease while that of anti-Delta1 Ab reduced the severity of the clinical disease. In contrast, administration of Jagged1-Fc protected from disease, that of Delta1-Fc exacerbated disease. Treatment with Jagged1-Fc was associated with increased IL-10-producing Ag-specific cells in the CNS, while anti-Jagged1 decreased the frequency of IL-10-producing cells. Treatment with Delta1-Fc increased Th1 cells in the CNS, while anti-Delta-1 decreased the frequency of Th1 cells. Manipulation of Delta1 or Jagged1 had no effect on the frequency of Th17 cells or FoxP3+ cells. Moreover, Jagged1 may play a role in CNS homeostasis because murine astrocytes specifically express Jagged1 that is up-regulated by TGF-β, whereas IFN-γ, TNF-α, and IL-17 decrease Jagged1 expression. Our study provides novel data about differential roles of Notch ligands in regulating inflammation in the periphery as well as in the CNS.

Regulation of innate and adaptive immunity by Notch

“…Neutralization of DLL4 during the induction of EAE resulted in an increase in the number of peripherally induced T Reg cells with a corresponding decrease in disease severity 91 . The effect was specific to DLL4, as DLL1 blockade had no effect on T H 17 and T Reg cell differentiation during EAE 92 . In addition, a more recent study showed that anti-DLL4 treatment prevented the development of, and even reverted, type 1 diabetes in nonobese diabetic (NOD) mice by inducing an increase in the number of DC-dependent de novo thymic T Reg cells 93 .…”

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

“…The effect of Notch signaling manipulation on the course of autoimmune inflammatory diseases has been examined. In a recent study, treatment with Jagged1-and Delta1-Fc fusion proteins differentially modulated the course of EAE (27). With ␥-secretase inhibitors, it has been shown that blocking the Notch pathway prevents Th1 polarization and IFN-␥ secretion (15).…”

Notch2 activation ameliorates nephrosis

“…The hybridoma cells were prepared as described above, and antibodies that reacted with mouse Notch2-transfected CHO cells, but not with untransfected CHO cells, were screened and cloned. All these mAbs were purified from ascites produced in pristan-primed ICR nude mice by the caprylic acid and ammonium sulphate precipitation method [36][37][38][39] . Two hundred and fifty micrograms of HMJ1-29 or control hamster IgG (UC8-1B9) and 100 mg of HMN1-12 or HMN2-29 were injected intraperitoneally on the indicated days.…”