Specification of T cell function during development

在胸腺细胞发育过程中，CD_4和CD_8共受体在确定CD_4辅助性或CD_8细胞毒性T细胞谱系中的作用仍然是T细胞发育生物学中一个有争议的方面。在这里，我们问的问题是，细胞毒性α-βT细胞系的特性是由CD8蛋白还是由调控CD8基因表达的转录控制元件决定的，这一概念我们称为‘共受体印迹’。为了评估共受体印记的可能性，我们在CD8a基因座位上敲入了CD4cDNA，并产生了突变小鼠，在该突变小鼠中，CD4蛋白的表达受内源性CD8a转录调控元件的调控。我们推测，如果细胞毒性T细胞系由CD8基因转录调控元件(与其编码的辅受体蛋白无关)指定，那么CD8基因上的CD4转录应能促进MHC-II类限制性胸腺细胞向细胞毒性T细胞系的发育。值得注意的是，与辅助的传统MHCII限制性CD4+T细胞不同，在CD8a基因独有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转录的瞬时终止扰乱了MHCII特异性TCR信号，从而允许细胞因子依赖于细胞因子对细胞毒T细胞命运的编程。这些结果证实了CD_4/CD_8谱系选择的动力学信号模型，并证明了CD_4辅助性T细胞或CD_8细胞毒性α-βT细胞的命运是由调控辅受体基因表达的转录调控元件决定的，即辅受体印迹。

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.