Dave V P, Allman D, Wiest D L, Kappes D J
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
J Immunol. 1999 May 15;162(10):5764-74.
Thymic selection is controlled in part by the avidity of the interaction between thymocytes and APCs. In agreement, the selective outcome can be modulated by altering the expression levels of selecting ligands on APCs. Here we test the converse proposition, i. e., whether changing TCR levels on thymocytes can alter the selective outcome. To this end, we have generated mice in which all thymocytes express two transgenic TCRs simultaneously (dual TCR-expressing (DTE) mice), the class I-restricted HY TCR and the class II-restricted AND TCR. Due to mutual dilution, surface expression levels of the two individual transgenic TCRs are diminished in DTE relative to single TCR-expressing mice. We find that thymic selection is highly sensitive to these reductions in TCR surface expression. Positive selection mediated by the AND and HY TCRs is severely impaired or abolished, respectively. Negative selection of the HY TCR in male DTE mice is also partly blocked, leading to the appearance of significant numbers of double positive thymocytes. Also, in the periphery of male, but not female, DTE mice, substantial numbers of single positive CD8bright cells accumulate, which are positively selected in the thymus but by a highly inefficient hemopoietic cell-dependent process. Overall our results favor the interpretation that the outcome of thymic selection is not determined solely by avidity and the resulting signal intensity, but is also constrained by other factors such as the nature of the ligand and/or its presentation by different subsets of APCs.
胸腺选择部分受胸腺细胞与抗原呈递细胞（APC）之间相互作用亲和力的控制。与此一致的是，通过改变APC上选择配体的表达水平可以调节选择结果。在此，我们测试相反的命题，即改变胸腺细胞上的TCR水平是否能改变选择结果。为此，我们构建了所有胸腺细胞同时表达两种转基因TCR的小鼠（双TCR表达（DTE）小鼠），即I类限制性HY TCR和II类限制性AND TCR。由于相互稀释，与单TCR表达小鼠相比，DTE小鼠中两个单独转基因TCR的表面表达水平降低。我们发现胸腺选择对TCR表面表达的这些降低高度敏感。由AND和HY TCR介导的阳性选择分别严重受损或被消除。雄性DTE小鼠中HY TCR的阴性选择也部分受阻，导致出现大量双阳性胸腺细胞。此外，在雄性而非雌性DTE小鼠的外周，大量单阳性CD8bright细胞积累，这些细胞在胸腺中被阳性选择，但通过一个高度低效的造血细胞依赖过程。总体而言，我们的结果支持这样的解释，即胸腺选择的结果不仅由亲和力和由此产生的信号强度决定，还受到其他因素的限制，如配体的性质和/或其由不同APC亚群呈递的情况。
