Urinary bladder epithelium antigen induces CD8+ T cell tolerance, activation, and autoimmune response
Urinary bladder epithelium antigen induces CD8+ T cell tolerance, activation, and autoimmune response
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DOI：
10.4049/jimmunol.178.1.539
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发表时间：
2007-01-01
影响因子：
4.4
通讯作者：
Luo, Yi
中科院分区：
文献类型：
--
作者：
Liu, Wujiang;Evanoff, David P.;Luo, Yi
长期以来，由于缺乏合适的动物模型，探索膀胱特定自身免疫机制的努力一直受到阻碍。为了更好地阐明这一问题，我们开发了一种新的转基因(TG)小鼠，命名为Uro-OVA小鼠，在膀胱上皮细胞上将模型Ag OVA表达为“自我”-Ag。Uro-OVA小鼠对OVA具有天然的耐受性，对OVA刺激无反应。过继转移的原始OVA特异性T细胞显示细胞增殖、活化和浸润，但没有膀胱组织病理学改变。相比之下，过继转移激活的OVA特异性T细胞可诱导OVA介导的组织膀胱炎。炎症膀胱中肥大细胞增多，肿瘤坏死因子-α、神经生长因子和P物质前体基因表达上调。为了进一步促进膀胱自身免疫的研究，我们将Uro-OVA小鼠与OVA特异性CD8(+)TCRTG小鼠(OT-I小鼠)杂交，产生了双TG系Uro-OVA/OT-I小鼠。后者的小鼠自然获得自身反应性OT-I CD8(+)T细胞的克隆性缺失(胸腺部分缺失，外周严重缺失)。尽管存在这种克隆性缺失，Uro-OVA/OT-I小鼠在10周龄时会自发发展为自身免疫性膀胱炎。进一步的研究表明，炎症的膀胱内含有浸润性的OT-I CD8(+)T细胞，在发生组织性膀胱炎之前，这些T细胞已经逃脱了克隆性缺失并获得了效应功能。综上所述，我们首次证明了膀胱上皮细胞主动向免疫系统递送自身抗原，并诱导CD8(+)T细胞耐受、激活和自身免疫反应。
The effort to explore the specific autoimmune mechanisms of urinary bladder has long been hindered due to a lack of proper animal models. To better elucidate this issue, we developed a novel line of transgenic (Tg) mice, designated as URO-OVA mice, that express the model Ag OVA as a "self"-Ag on the bladder epithelium. URO-OVA mice are naturally tolerant to OVA and show no response to OVA stimulation. Adoptive transfer of naive OVA-specific T cells showed cell proliferation, activation, and infiltration but no bladder histopathology. In contrast, adoptive transfer of activated OVA-specific T cells induced OVA-mediated histological bladder inflammation. Increased mast cells and up-regulated mRNA expressions of TNF-alpha, nerve growth factor, and substance P precursor were also observed in the inflamed bladder. To further facilitate bladder autoimmunity study, we crossbred URO-OVA mice with OVA-specific CD8(+) TCR Tg mice (OT-I mice) to generate a dual Tg line URO-OVA/OT-I mice. The latter mice naturally acquire clonal deletion for autoreactive OT-I CD8(+) T cells (partial deletion in the thymus and severe deletion in the periphery). Despite this clonal deletion, URO-OVA/OT-I mice spontaneously develop autoimmune cystitis at 10 wk of age. Further studies demonstrated that the inflamed bladder contained infiltrating OT-I CD8(+) T cells that had escaped clonal deletion and gained effector functions before developing histological bladder inflammation. Taken together, we demonstrate for the first time that the bladder epithelium actively presents self-Ag to the immune system and induces CD8(+) T cell tolerance, activation, and autoimmune response.