Jagged1 Suppresses Collagen-Induced Arthritis by Indirectly Providing a Negative Signal in CD8+ T Cells
Jagged1 Suppresses Collagen-Induced Arthritis by Indirectly Providing a Negative Signal in CD8+ T Cells
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DOI：
10.4049/jimmunol.0803765
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发表时间：
2009-03-15
影响因子：
4.4
通讯作者：
Yasutomo, Koji
中科院分区：
文献类型：
--
作者：
Kijima, Mika;Iwata, Akiko;Yasutomo, Koji
不同的Notch配体在功能性T细胞分化方面具有特征性能力。然而，每种Notch配体在自身免疫性疾病中的确切作用或治疗潜力在很大程度上是未知的。在这项研究中，我们研究了Jagged 1是否通过改变T细胞反应来调节胶原诱导的类风湿性关节炎（CIA）模型。在初始II型胶原（CII）免疫之前甚至之后注射可溶性Jagged 1编码质粒sJag 1-P可以抑制CIA疾病的严重程度。然而，这种处理并不抑制CII特异性CD 4（+）T细胞增殖和CH特异性Ab产生。CD 4（+）或CD 8（+）T细胞的耗竭改善了CIA的严重程度，sJag 1-P进一步改善了CD 4（+）T细胞耗竭小鼠的CIA，但CD 8（+）T细胞耗竭小鼠的CIA没有改善。尽管Jagged 1在体外不能直接抑制CD 8（+）T细胞的增殖，但注射OVA和Jagged 1编码质粒可抑制产生OVA特异性颗粒酶B的CD 8（+）T细胞的增殖。通过抗Jagged 1抗体阻断Jagged 1可加重CIA，而在缺乏CD 8（+）T细胞的情况下未观察到这种效应。这些数据表明，Jagged 1能够在体内向CD 8（+）T细胞传递间接负信号，这表明其在治疗CD 8（+）T细胞介导的疾病（包括类风湿性关节炎）中的治疗潜力。免疫学杂志，2009，182：3566-3572。
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 CH-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. The Journal of Immunology, 2009,182: 3566-3572.