The cellular and molecular mechanism of CD4/CD8 lineage commitment

A unique feature ofαβT-cell development is the central role played by clonally distributed T-cell receptors (TCR), which are encoded by somatically rearranged gene segments that produce a diverse, non-germline encoded set of receptors. Fate determination in individual T-cells is mediated by ligand-receptor signals that arise from unprogrammed genetic interactions, under conditions in which the relevant ligand concentration and the receptor affinity are not evolutionarily controlled. A precursor T-cell with a TCR that either fails to demonstrate appreciable self-reactivity or binds with high affinity to reasonably abundant self-peptide major histocompatibility complex (MHC)-ligands will undergo apoptosis. In contrast, a precursor T-cell that shows lower affinity to moderately abundant ligands will receive suitable signals for survival and maturation. Recently, we have developed a rapid in vitro two-step organ culture system that permits homogeneous populations of non-transformed precursor T-cells to undergo selective commitment to the CD4 or CD8 lineage. Using this model, we have shown that the choice of positively selected ab T-cells between the CD4 helper and CD8 cytotoxic lineages is regulated by the TCR signaling duration in response to self-peptides bound to the MHC.