A threshold for central T cell tolerance to an inducible serum protein
A threshold for central T cell tolerance to an inducible serum protein
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DOI：
10.4049/jimmunol.170.6.3007
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发表时间：
2003-03-15
影响因子：
4.4
通讯作者：
Williams, CB
中科院分区：
文献类型：
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作者：
Haribhai, D;Engle, D;Williams, CB
我们报告了一个自我银表达的诱导系统，检查血清蛋白水平和中央T细胞耐受性之间的关系。这种转基因方法是基于四环素调节的鸡蛋溶菌酶分泌形式的表达，标记有小鼠血红蛋白（Hb）表位。在缺乏四环素调节的反激活物的情况下，嵌合蛋白的血清水平极低（小于或等于0.1 ng/ml），小鼠对Hb（64-76）和溶菌酶表位均表现出部分耐受性。在反激活剂存在下，表达量增加到1.5 ng/ml，小鼠完全耐受。通过将这些小鼠与表达转基因tcr的菌株杂交，进一步研究了部分耐受性。在最低的Ag水平，3。L2tg T细胞（特异性Hb(64-76)/I-E-k）逃离胸腺，接近10%的CD4（+）脾细胞表达3。L2识别。相反，3A9 T细胞(对鸡蛋溶菌酶（46-61)/I-A(k)有特异性）被负选择完全消除。这些数据通过循环自身蛋白定义了抗原特异性T细胞阴性选择的耐受性阈值，其敏感性比先前证明的高100倍。他们认为，在极低水平的自身银暴露下，部分耐受是应答T细胞有限的结果，而不是简单的前体频率减少；耐受性阈值是T细胞特异性的。
We report an inducible system of self Ag expression that examines the relationship between serum protein levels and central T cell tolerance. This transgenic approach is based on tetracycline-regulated expression of a secreted form of hen egg lysozyme, tagged with a murine hemoglobin (Hb) epitope. In the absence of the tetracycline-regulated transactivator, serum levels of the chimeric protein are extremely low (less than or equal to0.1 ng/ml) and the mice show partial tolerance to both Hb(64-76) and lysozyme epitopes. In the presence of the transactivator, expression increases to 1.5 ng/ml and the mice are completely tolerant. Partial tolerance was further investigated by crossing these mice to strains expressing transgenic TCRs. At the lowest Ag levels, 3.L2tg T cells (specific for Hb(64-76)/I-E-k) escape the thymus and similar to10% of CD4(+) splenocytes express the 3.L2 TCR. In contrast, 3A9 T cells (specific for hen egg lysozyme(46-61)/I-A(k)) are completely eliminated by negative selection. These data define a tolerogenic threshold for negative selection of Ag-specific T cells by circulating self proteins that are 100-fold more sensitive than previously demonstrated. They suggest that partial tolerance at extremely low levels of self Ag exposure is the result of a restricted repertoire of responding T cells, rather than a simple reduction in precursor frequency; tolerogenic thresholds are T cell specific.