Development of the CD4 and CD8 lineage of T cells: Instruction versus selection

T cells bearing the αβ T cell receptor (TCR) can be divided into CD4⁺8^- and CD4^-8⁺ subsets which develop in the thymus from CD4⁺8⁺ precursors. The commitment to the CD4 and CD8 lineage depends on the binding of the αβ TCR to thymic major histocompatibility complex (MHC) coded class II and class I molecules, respectively. In an instructive model of lineage commitment, the binding of the αβ TCR, for instance to class I MHC molecules, would generate a specific signal instructing the CD4⁺8⁺ precursors to switch off the expression of the CD4 gene. In a selective model, the initial commitment, i.e. switching off the expression of either the CD4 or the CD8 gene would be a stochastic event which is then followed by a selective step rescuing only CD4⁺ class II and CD8⁺ class I specific T cells while CD4⁺ class I and CD8⁺ class II specific cells would have a very short lifespan. The selective model predicts that a CD8 transgene which is expressed in all immature and mature T cells should rescue CD4⁺ class I MHC specific T cells from cell death. We have performed experiments in CD8 transgenic mice which fail to support a selective model and we present data which show that the binding of the αβ TCR to thymic class I MHC molecules results in up-regulation of the TCR in the CD4⁺8⁺ population. Therefore, these experiments are consistent with an instructive model of lineage commitment.