Jagged1 Suppresses Collagen-Induced Arthritis by Indirectly Providing a Negative Signal in CD8+ T Cells

Abstract

Distinct Notch ligands possess a characteristic ability in terms of functional T cell differentiation. However, the precise role or the therapeutic potential of each Notch ligand in autoimmune diseases is largely unknown. In this study, we examined whether Jagged1 modulates a collagen-induced rheumatoid arthritis (CIA) model by altering T cell responses. The injection of a soluble Jagged1-encoding plasmid, sJag1-P, before or even after initial type II collagen (CII) immunization suppressed the disease severity of CIA. However, this treatment did not suppress CII-specific CD4+ T cell proliferation and CII-specific Ab production. Depletion of either CD4+ or CD8+ T cells ameliorated CIA severity and sJag1-P further improved CIA in CD4+ but not CD8+ T cell-depleted mice. Injection of OVA and Jagged1-encoding plasmids inhibited proliferation of OVA-specific granzyme B-producing CD8+ T cells, although Jagged1 could not directly inhibit CD8+ T cell proliferation in vitro. The blockade of Jagged1 by an anti-Jagged1 Ab exacerbated CIA, whereas this effect was not observed in the absence of CD8+ T cells. These data indicate that Jagged1 is able to deliver an indirect negative signal into CD8+ T cells in vivo, which suggests its therapeutic potential in the treatment of CD8+ T cell-mediated diseases, including rheumatoid arthritis.

Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance

“…DLL1 and 4 induced development of Th1 cells and effector memory CD8 + T-cells (15,25–29), whereas Jagged1 and 2 skewed T-cells into Th2, Treg, and anergic CD8 + T-populations (16,30–33). In agreement with the proposed immune inhibitory role of Jagged, we found that anti-Jagged overcame tumor-T-cell suppression through the induction of potentially immunogenic MDSC-LC.…”

“…In addition, NICD triggers a number of non-canonical responses (11,12). Binding of the Notch receptors on CD8 + T-cells to DLL ligands on antigen-presenting cells induces anti-tumor cytotoxic responses (13–15), whereas binding of Notch to Jagged members resulted in suppressive signals (16). The mechanism for this opposite effect remains unclear with possible explanations, including different kinetics of Notch activation or selectivity of DLL and Jagged ligands for Notch receptors.…”

Inhibition of Notch signalling ameliorates experimental inflammatory arthritis

“…The inhibition of Notch signalling by a γ-secretase inhibitor suppressed the progression of experimental autoimmune encephalomyelitis (EAE) 15. In contrast, overexpression of Jagged-1 suppressed CIA, and the blockade of Jagged-1 by an anti-Jagged-1 monoclonal antibody exacerbated CIA 11. Another report demonstrated that the administration of anti-Jagged-1 mAb exacerbated the clinical features of EAE, whereas DLL-1 mAb reduced disease severity 42.…”

“…The expression and activation of Notch occur in osteoarthritis cartilage and RA synoviocytes 7–10. Notch signalling is involved in the TNFα-induced proliferation of RA synoviocytes,10 and Jagged-1 can modulate collagen-induced arthritis (CIA) progression by affecting CD8 + T cell responses 11. T helper (Th) cells from RA patients exhibit an altered expression profile of Notch receptors and enhanced activation of Notch signalling 12.…”

Notch signalling pathways mediate synovial angiogenesis in response to vascular endothelial growth factor and angiopoietin 2

“…42 43 Jagged-1 modulates CIA by regulating T cell responses. 44 Notch-1 can mediate TNFα-induced synoviocyte proliferation, 42 45 and Notch-3 and DLL-1 mediate collagen-specific T-cell activation and altered T helper cells responses. 46 However, the mechanisms by which Notch signalling regulates angiogenesis in the inflamed joint remain to be elucidated.…”