The timing of TCRα expression critically influences T cell development and selection

Sequential rearrangement of the T cell receptor for antigen (TCR) β and α chains is a hallmark of thymocyte development. This temporal control is lost in TCR transgenics because the α chain is expressed prematurely at the CD4(−)CD8(−) double negative (DN) stage. To test the importance of this, we expressed the HYα chain at the physiological CD4(+)CD8(+) double positive (DP) stage. The reduced DP and increased DN cellularity typically seen in TCR transgenics was not observed when the α chain was expressed at the appropriate stage. Surprisingly, antigen-driven selection events were also altered. In male mice, thymocyte deletion now occurred at the single positive or medullary stage. In addition, no expansion of CD8αα intestinal intraepithelial lymphocytes (IELs) was observed, despite the fact that HY transgenics have been used to model IEL development. Collectively, these data establish the importance of proper timing of TCR expression in thymic development and selection and emphasize the need to use models that most accurately reflect the physiologic process.