Graded Attenuation of TCR Signaling Elicits Distinct Autoimmune Diseases by Altering Thymic T Cell Selection and Regulatory T Cell Function
Graded Attenuation of TCR Signaling Elicits Distinct Autoimmune Diseases by Altering Thymic T Cell Selection and Regulatory T Cell Function
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DOI：
10.4049/jimmunol.1000848
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发表时间：
2010-08-15
影响因子：
4.4
通讯作者：
Sakaguchi, Shimon
中科院分区：
文献类型：
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作者：
Tanaka, Satoshi;Maeda, Shinji;Sakaguchi, Shimon
具有70 kDa基因的z相关蛋白突变（skg突变）的小鼠在遗传上易于发展自身免疫性关节炎，这取决于环境。在一组具有该突变的小鼠中，70 kDa蛋白的z相关蛋白的量以及其在TCR刺激后的酪氨酸磷酸化以逐步方式从+/+、skg/+、skg/skg至skg/-小鼠降低。这种减少导致胸腺自身反应性T细胞和Foxp 3（+）天然调节性T细胞（T细胞）的阳性和阴性选择及其各自功能的分级改变。因此，即使在微生物清洁的环境中，skg/-小鼠也自发地发展自身免疫性关节炎，而skg/skg小鼠需要通过先天免疫刺激来表现疾病。Treg耗竭后，器官特异性自身免疫性疾病，特别是自身免疫性胃炎，主要发生在+/+中，在skg/+中发生率较低，但在患有其他自身免疫性疾病，特别是自身免疫性关节炎的skg/skg BALB/c小鼠中没有发生。与此相关的是，胃炎介导的TCR转基因T细胞在+/+中被阳性选择，在skg/+中较少，而在skg/skg BALB/c小鼠中没有。类似地，在糖尿病易感NOD小鼠的遗传背景下，糖尿病在+/+中自发发展，在skg/+中发病率较低，但在skg/skg小鼠中没有，而是死于关节炎。因此，TCR信号传导的分级衰减以渐进的方式改变自身免疫T细胞和天然T细胞的库和功能。它还改变了疾病发展对环境刺激的依赖性。这些发现共同提供了T细胞信号传导的遗传异常如何有助于自身免疫性疾病发展的模型。免疫学杂志，2010，185：2295-2305。
Mice with a mutation of the z-associated protein of 70 kDa gene (skg mutation) are genetically prone to develop autoimmune arthritis, depending on the environment. In a set of mice with the mutation, the amount of z-associated protein of 70 kDa protein as well as its tyrosine phosphorylation upon TCR stimulation decreased from +/+, skg/+, skg/skg, to skg/- mice in a stepwise manner. The reduction resulted in graded alterations of thymic positive and negative selection of self-reactive T cells and Foxp3(+) natural regulatory T cells (Tregs) and their respective functions. Consequently, skg/- mice spontaneously developed autoimmune arthritis even in a microbially clean environment, whereas skg/skg mice required stimulation through innate immunity for disease manifestation. After Treg depletion, organ-specific autoimmune diseases, especially autoimmune gastritis, predominantly developed in +/+, at a lesser incidence in skg/+, but not in skg/skg BALB/c mice, which suffered from other autoimmune diseases, especially autoimmune arthritis. In correlation with this change, gastritis-mediating TCR transgenic T cells were positively selected in +/+, less in skg/+, but not in skg/skg BALB/c mice. Similarly, on the genetic background of diabetes-prone NOD mice, diabetes spontaneously developed in +/+, at a lesser incidence in skg/+, but not in skg/skg mice, which instead succumbed to arthritis. Thus, the graded attenuation of TCR signaling alters the repertoire and the function of autoimmune T cells and natural Tregs in a progressive manner. It also changes the dependency of disease development on environmental stimuli. These findings collectively provide a model of how genetic anomaly of T cell signaling contributes to the development of autoimmune disease. The Journal of Immunology, 2010, 185: 2295-2305.