T cell progenitors migrate from the bone marrow to the thymus, where the entire process of maturation occurs (Fig. 1). The process of T lymphocyte maturation has some unique features, primarily related to the specificity of different subsets of T cells for peptides dis played by different classes of MHC molecules.

Fig1. Steps in the maturation and selection of major histocompatibility complex (MHC)–restricted T lymphocytes. The maturation of T lymphocytes in the thymus proceeds through sequential steps often defined by the expression of the CD4 and CD8 coreceptors. The T cell receptor (TCR) β chain is first expressed at the double-negative pre-T cell stage, and the complete T cell receptor is expressed in double-positive cells. The pre-TCR consists of the TCR β chain associated with a protein called pre-Tα. Maturation culminates in the development of CD4+ and CD8+ single-positive T cells. As with B cells, failure to express antigen receptors at any stage leads to death of the cells by apoptosis. Only class II MHC is shown for negative selection, but the same process eliminates self-reactive class I MHC–restricted CD8+ T cells.

Early Steps in T Cell Maturation

 The least developed progenitors in the thymus are called pro-T cells or double-negative T cells because they do not express CD4 or CD8. These cells expand in number mainly under the influence of IL-7 produced in the thy mus. TCR β gene recombination, mediated by the VDJ recombinase, occurs in some of these double-negative cells. (The γδ T cells undergo similar recombination involving TCR γ and δ loci, but they belong to a distinct lineage and are not discussed further.) If VDJ recombination is successful in one of the two inherited loci and a TCR β chain protein is synthesized, it is expressed on the cell surface in association with an invariant protein called pre-Tα, to form the pre-TCR complex of pre-T cells. If the recombination in one of the two inherited loci is not successful, recombination will take place on the other locus. If that too fails and a complete TCR β chain is not produced in a pro-T cell, the cell dies.

The pre-TCR complex delivers intracellular signals once it is assembled, similar to the signals from the pre-BCR complex in developing B cells. These signals promote survival, proliferation, and TCR α gene recombination and inhibit VDJ recombination in the second β chain locus (allelic exclusion). Failure to express the α chain and the complete TCR again results in death of the cell. The surviving cells express the complete αβ TCR and both the CD4 and CD8 coreceptors; these cells are called double-positive T cells. 

Selection of Mature T Cells

Different clones of double-positive T cells express different αβ TCRs. If the TCR of a T cell recognizes an MHC molecule in the thymus, which must be a self MHC molecule displaying a self-peptide, and if the interaction is of low or moderate affinity, this T cell is selected to survive. T cells that do not recognize an MHC molecule in the thymus die by apoptosis; these T cells would not be useful because they would be incapable of seeing MHC-displayed cell-associated antigens in that individual. This preservation of self MHC–restricted (i.e., useful) T cells is the process of positive selection. During this process, T cells whose TCRs recognize class I MHC–peptide complexes preserve the expression of CD8, the coreceptor that binds to class I MHC, and lose expression of CD4, the coreceptor specific for class II MHC molecules. Conversely, if a T cell recognizes class II MHC–peptide complexes, this cell maintains expression of CD4 and loses expression of CD8. Thus, what emerges are single-positive T cells (or single-positive thymocytes), which are either CD8+ class I MHC restricted or CD4+ class II MHC restricted. During positive selection, the T cells also become committed to different functional fates: the CD8+ T cells will differentiate into CTLs on activation, and the CD4+ cells will differentiate into cytokine-producing helper T cells.

Immature, double-positive T cells whose receptors strongly recognize MHC-peptide complexes in the thymus undergo apoptosis. This is the process of negative selection, and it serves to eliminate T lymphocytes that could react in a harmful way against self proteins that are expressed in the thymus. If a T cell that recognizes a self peptide with high avidity were allowed to mature, recognition of the same self antigen in the periphery could lead to harmful immune responses against self tissues, so such a T cell must be eliminated. Some immature T cells that recognize self antigens in the thymus do not die but develop into regulatory T cells . Most of the proteins present in the thymus are self proteins, because foreign (microbial and tumor) antigens are typically captured and taken to secondary lymphoid organs. Some of these self proteins are present throughout the body, and others are proteins that are restricted to particular tissues but are expressed in thymic epithelial cells by special mechanisms.

It may seem surprising that both positive selection and negative selection are mediated by recognition of the same set of self MHC–self peptide complexes in the thymus. The two factors that determine the choice between positive and negative selection are the affinity of the TCR and the concentration of the self antigen in the thymus. If a TCR strongly recognizes an abundant self antigen in the thymus, that T cell will be negatively selected, which makes sense because strong recognition of an abundant self antigen has the potential for causing autoimmunity. However, if a TCR recognizes a self peptide–self MHC complex weakly, that T cell will be positively selected because there is a reasonable chance the T cell will recognize a foreign peptide presented by self MHC strongly. This is the process that gives rise to the repertoire of functional T cells.