Liu Yi-Hsia, Mölzer Christine, Makinen Kimmo, Kamoi Koju, Corbett Clare L C, Klaska Izabela P, Reid Delyth M, Wilson Heather M, Kuffová Lucia, Cornall Richard J, Forrester John V
Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
Front Immunol. 2020 Sep 4;11:2071. doi: 10.3389/fimmu.2020.02071. eCollection 2020.
We specify the clinical features of a spontaneous experimental autoimmune uveitis (EAU) model, in which foreign hen-egg lysozyme (HEL) is expressed in the retina, controlled by the promoter for interphotoreceptor retinol binding protein (IRBP). We previously reported 100% P21 (post-partum day) IRBP:HEL single transgenic (sTg) mice, when crossed to transgenic T cell receptor mice (3A9) generating the double transgenic (dTg) genotype, develop EAU despite profound lymphopenia (thymic HEL-specific T cell deletion). In this work, we characterized the immune component of this model and found conventional dTg CD4+ T cells were less anergic than those from 3A9 controls. Furthermore, prior HEL-activation of 3A9 anergic T cells (T) rendered them uveitogenic upon adoptive transfer (Tx) to sTg mice, while antigen-experienced (AgX, dTg), but not naïve (3A9) T cells halted disease in P21 dTg mice. Flow cytometric analysis of the AgX cells elucidated the underlying pathology: FoxP3+CD25CD4+ T regulatory cells (T) comprised ∼18%, while FR4+CD73+FoxP3-CD25CD4+ T comprised ∼1.2% of total cells. Further T-enrichment (∼80%) of the AgX population indicated FoxP3+CD25CD4+ T played a key role in EAU-suppression while FoxP3-CD25CD4+ T cells did not. Here we present the novel concept of dual immunological tolerance where spontaneous EAU is due to escape from anergy with consequent failure of T induction and subsequent imbalance in the [T:T] cell ratio. The reduced numbers of T, normally sustaining T to prevent autoimmunity, are the trigger for disease, while immune homeostasis can be restored by supplementation with AgX, but not naïve, antigen-specific T.
我们详细描述了一种自发性实验性自身免疫性葡萄膜炎（EAU）模型的临床特征，在该模型中，外源鸡卵溶菌酶（HEL）在视网膜中表达，由光感受器间视黄醇结合蛋白（IRBP）的启动子控制。我们之前报道，100%的产后第21天（P21）IRBP:HEL单转基因（sTg）小鼠，与产生双转基因（dTg）基因型的转基因T细胞受体小鼠（3A9）杂交后，尽管存在严重的淋巴细胞减少（胸腺中HEL特异性T细胞缺失），仍会发生EAU。在这项研究中，我们对该模型的免疫成分进行了表征，发现传统的dTg CD4+ T细胞比3A9对照组的细胞更少处于无反应状态。此外，对3A9无反应性T细胞（T）进行预先的HEL激活后，将其过继转移（Tx）到sTg小鼠时会使其具有致葡萄膜炎性，而经历过抗原刺激（AgX，dTg）但非未接触过抗原（3A9）的T细胞会使P21 dTg小鼠的疾病停止。对AgX细胞进行流式细胞术分析揭示了潜在的病理情况：FoxP3+CD25CD4+调节性T细胞（T）约占总细胞的18%，而FR4+CD73+FoxP3-CD25CD4+ T约占总细胞的1.2%。对AgX群体进行进一步的T细胞富集（约80%）表明，FoxP3+CD25CD4+ T在EAU抑制中起关键作用，而FoxP3-CD25CD4+ T细胞则不然。在此，我们提出了双重免疫耐受的新概念，即自发性EAU是由于从无反应状态逃逸，导致T细胞诱导失败以及随后[T:T]细胞比例失衡。正常情况下维持T细胞以预防自身免疫的T细胞数量减少是疾病的触发因素，而通过补充AgX而非未接触过抗原的抗原特异性T细胞可以恢复免疫稳态。
