T cell self-reactivity during thymic development dictates the timing of positive selection.
T cell self-reactivity during thymic development dictates the timing of positive selection.
复制标题
DOI：
10.7554/elife.65435
复制
发表时间：
2021-04-22
期刊：
影响因子：
7.7
通讯作者：
Robey EA
中科院分区：
文献类型：
--
作者：
Lutes LK;Steier Z;McIntyre LL;Pandey S;Kaminski J;Hoover AR;Ariotti S;Streets A;Yosef N;Robey EA
T 细胞根据其自身反应性程度进行功能调整是在胸腺的正选择过程中建立的，尽管尚不清楚具有相对较低和较高自身反应性的胸腺细胞的正选择有何不同。此外，预选胸腺细胞对低亲和力配体高度敏感，但其增强 T 细胞受体 (TCR) 敏感性的机制尚不完全清楚。在这里，我们发现，与具有高自身反应性的小鼠胸腺细胞相比，具有低自身反应性的小鼠胸腺细胞经历更短的TCR信号并且更慢地完成阳性选择。此外，我们提供的证据表明，自我反应性低的细胞在成熟时保留了预选基因表达特征，包括先前涉及调节 TCR 敏感性的基因和一组新的离子通道基因。我们的结果表明，自我反应性低的胸腺细胞在正选择过程中下调 TCR 敏感性的速度更慢，并将膜离子通道表达与胸腺细胞自我反应性和正选择过程中的进展相关联。
Functional tuning of T cells based on their degree of self-reactivity is established during positive selection in the thymus, although how positive selection differs for thymocytes with relatively low versus high self-reactivity is unclear. In addition, preselection thymocytes are highly sensitive to low-affinity ligands, but the mechanism underlying their enhanced T cell receptor (TCR) sensitivity is not fully understood. Here we show that murine thymocytes with low self-reactivity experience briefer TCR signals and complete positive selection more slowly than those with high self-reactivity. Additionally, we provide evidence that cells with low self-reactivity retain a preselection gene expression signature as they mature, including genes previously implicated in modulating TCR sensitivity and a novel group of ion channel genes. Our results imply that thymocytes with low self-reactivity downregulate TCR sensitivity more slowly during positive selection, and associate membrane ion channel expression with thymocyte self-reactivity and progress through positive selection.