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.
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