Tracking the role of Aire in immune tolerance to the eye with a TCR transgenic mouse model.
Tracking the role of Aire in immune tolerance to the eye with a TCR transgenic mouse model.
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用TCR转基因小鼠模型追踪Aire在眼免疫耐受中的作用。
DOI：
10.1073/pnas.2311487121
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发表时间：
2024-01-30
影响因子：
11.1
通讯作者：
Defranco, Anthony L.
中科院分区：
文献类型：
--
作者：
Yin, Mianmian;Smith, Jennifer A.;Chou, Marissa;Chan, Jackie;Jittayasothorn, Yingyos;Gould, Douglas B.;Caspi, Rachel R.;Anderson, Mark S.;Defranco, Anthony L.
为了模拟人类自身免疫性疾病，这种疾病通常表现为多基因遗传，我们创建了Aire和Lyn突变的小鼠，它们分别改变了T细胞的胸腺耐受性和T细胞的外周活化。50%的小鼠自发地产生了眼部自身免疫。TCR转基因小鼠能够识别关键的视网膜自身抗原，以便更精确地定义免疫耐受是如何受损的。在没有Aire突变的小鼠中，由于对视网膜蛋白的识别，转基因T细胞几乎全部在胸腺发育过程中死亡，少数成为可抑制疾病发生的调节性T细胞。在Aire突变后，这些耐受机制丧失，这导致了很强的疾病外显率。在两种免疫耐受途径中存在部分缺陷的小鼠（AireGW/+Lyn - / -小鼠）中，大约有一半的小鼠由于T细胞对空气调节的光感受器间类视黄酸结合蛋白（IRBP）的反应性而自发地发生严重的视网膜损伤。对IRBP显性表位特异性的CD4+ T细胞的单细胞T细胞受体（TCR）测序显示，疾病小鼠中自身抗原特异性TCR具有显著的多样性，且克隆扩增更大。用扩增的中等亲和力的irbp特异性TCR （P2.U2）构建的TCR转基因小鼠对胸腺细胞表现出强烈但不完全的负选择。这种负选择在IRBP−/−小鼠中不存在，而在AireGW/+小鼠中存在严重缺陷。大多数P2。U2+/−mice和所有P2.U。2+/−AireGW/+小鼠迅速发生视网膜和相邻葡萄膜炎症（葡萄膜炎）。胸腺中依赖空气的IRBP表达也促进Treg分化，但这种命运决定的生态位很小，这表明抗原呈递导致阴性选择与胸腺Treg分化的差异，以及阴性选择在预防视网膜自身免疫性疾病中的更大作用。
To model human autoimmune disease, which typically exhibits multigenic inheritance, we created mice with mutations in Aire and Lyn, which respectively alter thymic tolerance of T cells and peripheral activation of T cells. Fifty percent of these mice spontaneously develop eye autoimmunity. TCR transgenic mice were created that recognize the critical retinal autoantigen in order to define more precisely how immune tolerance is compromised. In mice without the Aire mutation, the transgenic T cells almost all die during their thymic development due to recognition of the retinal protein, and a small number become regulatory T cells, which can inhibit disease onset. Upon mutation of Aire, these tolerance mechanisms are lost and this results in strong disease penetrance. Roughly one-half of mice with partial defects in two immune tolerance pathways (AireGW/+Lyn−/− mice) spontaneously develop severe damage to their retinas due to T cell reactivity to Aire-regulated interphotoreceptor retinoid–binding protein (IRBP). Single-cell T cell receptor (TCR) sequencing of CD4+ T cells specific for a predominate epitope of IRBP showed a remarkable diversity of autoantigen-specific TCRs with greater clonal expansions in mice with disease. TCR transgenic mice made with an expanded IRBP-specific TCR (P2.U2) of intermediate affinity exhibited strong but incomplete negative selection of thymocytes. This negative selection was absent in IRBP−/− mice and greatly defective in AireGW/+ mice. Most P2.U2+/− mice and all P2.U.2+/−AireGW/+ mice rapidly developed inflammation of the retina and adjacent uvea (uveitis). Aire-dependent IRBP expression in the thymus also promoted Treg differentiation, but the niche for this fate determination was small, suggesting differences in antigen presentation leading to negative selection vs. thymic Treg differentiation and a stronger role for negative selection in preventing autoimmune disease in the retina.
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影响因子：
12.8
作者：
Pillai S
通讯作者：
Pillai S
DOI：
10.1073/pnas.1300617110
发表时间：
2013-08-27
影响因子：
11.1
作者：
Lamagna, Chrystelle;Scapini, Patrizia;Lowell, Clifford A.
通讯作者：
Lowell, Clifford A.
影响因子：
32.4
作者：
Horai R;Zárate-Bladés CR;Dillenburg-Pilla P;Chen J;Kielczewski JL;Silver PB;Jittayasothorn Y;Chan CC;Yamane H;Honda K;Caspi RR
通讯作者：
Caspi RR
影响因子：
32.4
作者：
Leventhal DS;Gilmore DC;Berger JM;Nishi S;Lee V;Malchow S;Kline DE;Kline J;Vander Griend DJ;Huang H;Socci ND;Savage PA
通讯作者：
Savage PA
影响因子：
32.4
作者：
Leonard JD;Gilmore DC;Dileepan T;Nawrocka WI;Chao JL;Schoenbach MH;Jenkins MK;Adams EJ;Savage PA
通讯作者：
Savage PA