T-cell development and the CD4–CD8 lineage decision

Cell-fate decisions are controlled typically by conserved receptors that interact with co-evolved ligands. Therefore, the lineage-specific differentiation of immature CD4+CD8+ T cells into CD4+ or CD8+ mature T cells is unusual in that it is regulated by clonally expressed, somatically generated T-cell receptors (TCRs) of unpredictable fine specificity. Yet, each mature T cell generally retains expression of the co-receptor molecule (CD4 or CD8) that has an MHC-binding property that matches that of its TCR. Two models were proposed initially to explain this remarkable outcome — 'instruction' of lineage choice by initial signalling events or 'selection' after a stochastic fate decision that limits further development to cells with coordinated TCR and co-receptor specificities. Aspects of both models now appear to be correct; mistake-prone instruction of lineage choice precedes a subsequent selection step that filters out most incorrect decisions.