Like developing B cells, developing thymocytes pass through a series of distinct stages. These are marked by changes in the status of the T-cell receptor genes and in the expression of the T-cell receptor, and by changes in the expression of cell-surface proteins such as the CD3 complex (see Section 7-7) and the co-receptor proteins CD4 and CD8 (see Section 4-18). These surface changes reflect the state of functional maturation of the cell, and particular combinations of cell-surface proteins are used as markers for T cells at different stages of differentiation. The principal stages are summarized in Fig. 8.20. Two distinct lineages of T cells—α:βand γ:δ, which have different types of T-cell receptor chains—are produced early in T-cell development. Later, α:β T cells develop into two distinct functional subsets—CD4 T cells and CD8 T cells.
When progenitor cells first enter the thymus from the bone marrow, they lack most of the surface molecules characteristic of mature T cells, and their receptor genes are not rearranged. These cells give rise to the major population of α:β T cells and the minor population of γ:δ T cells. If injected into the peripheral circulation, these lymphoid progenitors can even give rise to B cells and NK cells, although it is uncertain whether individual thymic progenitor cells retain this multipotency, or whether the progenitor cell population consists of a mixture of cells, only some of which are fully committed to the αβor γδ T-cell lineage.
Interactions with the thymic stroma trigger an initial phase of differentiation along the T-cell lineage pathway, followed by cell proliferation and the expression of the first cell-surface molecules specific for T cells, for example, CD2 and (in mice) Thy-1. At the end of this phase, which can last about a week, the thymocytes bear distinctive markers of the T-cell lineage but do not express any of the three cell-surface markers that define mature T cells. These are the CD3:T-cell receptor complex and the co-receptors CD4 or CD8. Because of the absence of CD4 and CD8, such cells are called double-negative thymocytes (see Fig. 8.20).
Fig. 8.20 Two distinct lineages of thymocytes are produced in the thymus. CD4, CD8, and T-cell receptor complex molecules (CD3, and the T-cell receptor α and β chains) are important cell-surface molecules for identifying thymocyte subpopulations. The earliest cell population in the thymus does not express any of these proteins, and because these cells do not express CD4 or CD8, they are called ‘double-negative’ thymocytes. These cells include precursors that give rise to two T-cell lineages: the minority population of γ:δ T cells (which lack CD4 or CD8 even when mature), and the majority α:β T-cell lineage. The development of prospective α:β T cells proceeds through stages in which both CD4 and CD8 are expressed by the same cell; these are known as ‘double-positive’ thymocytes. These cells enlarge and divide. Later, they become small resting double-positive cells that express low levels of the T-cell receptor. Most thymocytes die within the thymus after becoming small double-positive cells, but those cells whose receptors can interact with self peptide:self MHC molecular complexes lose expression of either CD4 or CD8 and increase the level of expression of the T-cell receptor. The outcome of this process is the ‘single-positive’ thymocytes, which, after maturation, are exported from the thymus as mature single-positive CD4 or CD8 T cells.