The regulation and function of the CD4 coreceptor during T lymphocyte development.

The data reviewed in this chapter suggest that the primary developmental function of the CD4 and CD8 coreceptors is to improve the efficacy by which a thymocyte recognizes peptide/MHC. During positive selection, DP thymocytes down-regulate expression of either CD4 or CD8 in response to signals that originate from the TCR/coreceptor complex. Experiments with transgenic and MHC-null mice have shown that coreceptor down-regulation and lineage commitment can occur stochastically in a manner that is independent of TCR specificity for MHC. Nevertheless, the positive selection of a given thymocyte is contingent on sustained expression of the coreceptor that is appropriate for the MHC specificity of its TCR. In most cases, loss of the required coreceptor blocks developmental progression and results in thymocyte apoptosis. CD4 expression is controlled by both positive and negative regulatory sequences embedded in the CD4 gene and it is likely that similar sequences regulate the CD8 gene. The down-regulation of coreceptor expression is coupled to a functional commitment which ensures that mature CD4+ T cells have a helper phenotype and CD8+ T cells have a cytotoxic phenotype. The molecular basis for this coupling and the identity of the switching mechanism which governs coreceptor regulation remain to be determined.