Specification of T cell function during development

在胸腺细胞发育过程中，CD4和CD8辅助受体在指定CD4辅助细胞或CD8细胞毒性T细胞谱系中的作用仍然是T细胞发育生物学中有争议的一个方面。在这里，我们询问细胞毒性α - β T细胞谱系的特异性是由CD8蛋白决定的，还是由调节CD8基因表达的转录控制元件决定的，我们将这一概念称为“辅助受体印记”。为了评估共受体印迹的可能性，我们将Cd4 cDNA敲入Cd8a基因位点，并产生Cd4蛋白表达受内源性Cd8a转录控制元件调节的突变小鼠。我们推断，如果细胞毒性T细胞谱系是由Cd8基因转录控制元件指定的（不管它编码的辅助受体蛋白是什么），那么Cd8位点的CD4转录应该促进MHC ii类限制性胸腺细胞向细胞毒性T细胞谱系的发展。值得注意的是，与具有辅助作用的传统mhcii限制性CD4+ T细胞不同，在CD4完全由Cd8a基因编码的小鼠中产生的mhcii限制性CD4+ T细胞具有细胞毒性。此外，我们提供的证据表明，在阳性选择过程中，Cd8a基因编码的CD4转录的短暂终止会破坏mhcii特异性TCR信号，从而允许细胞因子依赖性的细胞毒性T细胞命运编程。这些结果证实了CD4/CD8谱系选择的动力学信号模型，并表明CD4辅助细胞或CD8细胞毒性α - β T细胞的命运是由调节辅助受体基因表达的转录控制元件决定的，即辅助受体印迹。

The role of CD4 and CD8 coreceptors in specifying the CD4 helper or CD8 cytotoxic T cell lineages during thymocyte development remains a controversial aspect of T cell developmental biology. Here we asked whether specification of the cytotoxic alpha-beta T cell lineage is determined by the CD8 protein or by the transcriptional control elements that regulate Cd8 gene expression, a concept we refer to as 'Coreceptor Imprinting'. To assess the possibility of coreceptor imprinting we knocked in Cd4 cDNA into the Cd8a gene locus and generated mutant mice in which CD4 protein expression is regulated by endogenous Cd8a transcriptional control elements. We reasoned that if the cytotoxic T cell lineage is specified by Cd8 gene transcriptional control elements (regardless of the coreceptor protein it encoded), then CD4 transcription from the Cd8 locus should promote the development of MHC class II-restricted thymocytes into the cytotoxic T cell lineage. Remarkably, unlike conventional MHCII-restricted CD4+ T cells that are helpers, MHCII-restricted CD4+ T cells generated in mice in which CD4 was exclusively encoded by the Cd8a gene were cytotoxic. Further, we provide evidence that transient termination of Cd8a gene-encoded CD4 transcription disrupts MHCII-specific TCR signals during positive selection permits a cytokine-dependent programming of the cytotoxic T cell fate. These results confirm the kinetic signaling model of CD4/CD8 lineage choice and demonstrate that specification of CD4 helper or CD8 cytotoxic alpha-beta T cell fate is dictated by the transcriptional control elements that regulate coreceptor gene expression, i.e. coreceptor imprinting.