cells bearing the β£β€ T-cell receptor (TCR) complex recognize antigen in the form of peptide fragments bound to proteins encoded by the host major histocompatibility complex (MHC). Because of the random recombination events regulating generation of the specificity of TCRβ£ and TCRβ€ proteins, T cells are screened for their ability to recognize peptide-self-MHC complexes at an immature stage within the thymus. Only cells that bear antigen receptors with appropriate affinity/avidity for peptide-self-MHC complexes complete their maturation and form the peripheral T-cell pool. This screening system involves discrete forms of selection, with cells that bear TCRs with no affinity for peptide-MHC destined to die by neglect, whereas thymocytes capable of recognition are either positively or negatively selected, depending on the degree of affinity or avidity of the TCR for MHC-peptide complexes [1][2][3][4] .
The target population for T-cell selection in the thymus comprises small, non-dividing thymocytes of a CD4 Ο© CD8 Ο© TCRβ£β€ lo phenotype 5 . If rescued by positive selection, these cells -which have a relatively short life-span of three to five days 6 -are induced to differentiate further to become functionally mature and long-lived T cells in the periphery. However, the same CD4 Ο© CD8 Ο© TCRβ£β€ lo stage represents a developmental window in which thymocytes are also susceptible to negative selection 7 , and it is clear that both selection events are dependent upon signals received via the TCRβ£β€ complex, resulting in a variety of phenotypic and genotypic events (Fig. 1). Thus, the mechanisms by which both forms of selection are able to occur without cancelling each other out is a major paradox in thymus biology.
The process of positive selection is a crucial stage in intrathymic T-cell development because it not only determines the specificity of β£β€T cells in the periphery, but also controls the phenotype and functional specialization of thymocytes into CD4 Ο© T helper cells and CD8 Ο© cytotoxic T lymphocytes (CTLs) 8,9 . Although the continued maturation of CD4 Ο© CD8 Ο© thymocytes is dependent on TCRβ£β€-MHC interactions, the nature of which have been reviewed elsewhere 1-3 , it is becoming increasingly apparent that positive selection is a multistage process, involving sustained interactions with the thymic microenvironment [10][11][12][13] . However, few studies have addressed events after the initial triggering of positive selection or post-selection events operating on newly generated CD4 Ο© and CD8 Ο© thymocytes.
Here, we describe recent findings concerning the mechanisms regulating the maturation of CD4 Ο© CD8 Ο© thymocytes. We propose a model in which the positive selection process can be split into three discrete phases: initiation, completion and post-selection differentiation. In addition, we highlight the role played by thymic stromal cells in these phases of positive selection.