Regulation of TCR-induced IFN-γ release from islet-reactive non-obese diabetic CD8+ T cells by prostaglandin E2 receptor signaling
Regulation of TCR-induced IFN-γ release from islet-reactive non-obese diabetic CD8+ T cells by prostaglandin E2 receptor signaling
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DOI：
10.1093/intimm/12.6.851
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发表时间：
2000-06-01
影响因子：
4.4
通讯作者：
von Grafenstein, H
中科院分区：
文献类型：
--
作者：
Ganapathy, V;Gurlo, T;von Grafenstein, H
前列腺素（PG）在组织损伤和炎症期间释放，并在许多点抑制免疫反应。PG可能是几个因素之一，保护不仅对损伤引起的，但也自发的，器官特异性自身免疫性疾病。在这里，我们发现PGE（2）的产生，通常在胰岛中以非常低的速率产生，在非肥胖糖尿病（NOD）小鼠的炎症胰岛中显著增加。我们研究了PGE（2）在控制胰岛反应性NOD CD 8（+）T细胞的TCR依赖性IFN-γ释放中的可能作用。PGE（2）抑制抗TCR抗体触发的IFN-γ从CD 8（+）T细胞克隆8D 8和多克隆细胞毒性T淋巴细胞（CTL）的释放。使用受体亚型选择性激动剂，我们提供证据表明PGE（2）的作用是由EP 2和EP 4受体介导的，这两种受体都与细胞内cAMP产生的增加相关联。cAMP类似物8-Br-cAMP和Sp-cAMPS模拟EP 2/EP 4受体激动剂的作用，以剂量依赖性方式抑制TCR触发的IFN-γ从NOD CD 8（+）T细胞释放。PGE（2）的抑制作用在很大程度上可被IL-2逆转，并随着TCR刺激强度的增加而减弱。静息CTL对PGE（2）的敏感性高于新近扩增的CTL，NOD CD 8（+）T细胞对PGE（2）的不敏感时间长于BALB/c细胞。我们的研究表明，PGE（2）可能是控制T细胞局部活化的调节网络的一部分，并可能在胰岛自身免疫的发展或耐受的维持之间的平衡中发挥作用。
Prostaglandins (PG) are released during tissue injury and inflammation, and inhibit immune responses at many points. PG may be one of several factors that protect not only against injury-induced, but also spontaneous, organ-specific autoimmune disease. Here we show that the production of PGE(2), normally produced at a very low rate in islets of Langerhans, is significantly increased in inflamed islets of non-obese diabetic (NOD) mice, We investigated a possible role of PGE(2) in controlling TCR-dependent release of IFN-gamma from islet-reactive NOD CD8(+) T cells. PGE(2) inhibited anti-TCR antibody-triggered release of IFN-gamma from CD8(+) T cell clone 8D8 and from polyclonal cytotoxic T lymphocytes (CTL), Using receptor subtype selective agonists, we present evidence that the effect of PGE(2) is mediated by EP2 and EP4 receptors, both of which are coupled to an increase In intracellular cAMP production. The cAMP analogs 8-Br-cAMP and Sp-cAMPS mimic the effect of EP2/EP4 receptor agonists, inhibiting TCR-triggered IFN-gamma release from NOD CD8(+) T cells in a dose-dependent manner. The inhibitory effect of PGE(2) was largely reversed by IL-2 added at the time of culture initiation and decreased with increasing strength of stimulation through the TCR, Resting CTL were more sensitive to PGE, than recently expanded CTL and NOD CD8(+) T cells remained insensitive to PGE(2) for a longer time than BALB/c cells. Our study suggests that PGE(2) may be part of a regulatory network that controls local activation of T cells and may play a role in the balance between the development of islet autoimmunity or maintenance of tolerance.