Jagged1 suppresses collagen-induced arthritis by indirectly providing a negative signal in CD8+ T cells.
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.
Kijima
Mika
M
Department of Immunology and Parasitology, University of Tokushima Graduate School, Tokushima, Japan.
Iwata
Akiko
A
Maekawa
Yoichi
Y
Uehara
Hisanori
H
Izumi
Keisuke
K
Kitamura
Akiko
A
Yagita
Hideo
H
Chiba
Shigeru
S
Shiota
Hiroshi
H
Yasutomo
Koji
K
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use*; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology / Q000627:therapeutic use*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use*; D000072100:Jagged-1 Protein; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008212:Lymphocyte Depletion; D008297:Male; D008565:Membrane Proteins / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use
D002135:Calcium-Binding Proteins; D006131:Growth Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins; D019444:Vaccines, DNA