Duration of TCR signaling controls CD4-CD8 lineage differentiation in vivo

The duration of T cell receptor (TCR) signaling is thought to be important for thymocyte differentiation into the CD4 or CD8 lineage. However, the in vivo relevance of this hypothesis is unclear. Here we divided T cell positive selection into genetically separable developmental steps by confining TCR signal transduction to discrete thymocyte developmental windows. TCR signals confined to the double-positive thymocyte stage promoted CD8, but not CD4, lineage differentiation. Major histocompatibility complex (MHC) class II-restricted thymocytes were, instead, redirected into the CD8 lineage. These findings support the hypothesis that distinct kinetics of MHC class I- and MHC class II-induced TCR signals direct intrathymic developmental decisions.