In DN3 thymocytes (see Fig. 8.18), the expressed β chains pair with a surrogate pre-T-cell receptor α chain called pTα (pre-T-cell α), which allows the assembly of a complete pre-T-cell receptor (pre-TCR) that is analogous in structure and function to the pre-B-cell receptor. The pre-TCR is expressed on the cell surface in a complex with the CD3 molecules that provide the signaling components of T-cell receptors (see Section 7-7). As with the preB-cell receptor, the assembly of the CD3:pre-T-cell receptor complex causes constitutive signaling that does not require interaction with a ligand. Recent structural evidence shows that the pre-TCR forms dimers in a manner similar to pre-BCR dimerization. The pTα Ig domain makes two important contacts. It associates with the constant-region Ig domain of the Vβsubunit to form the pre-TCR itself. A distinct surface of the pre-Tα then binds to a Vβ domain from another pre-TCR molecule, forming a bridge between two different pre-TCRs. The region of contact with the Vβ involves residues that are highly conserved across many Vβ families. In this way, expression of the pre-TCR induces ligand-independent dimerization, which leads to cell proliferation, the arrest of further β-chain gene rearrangement, and the expression of both CD8 and CD4. These double-positive thymocytes make up the vast majority of thymocytes. Once the large double-positive thymocytes have ceased to proliferate and have become small double-positive cells, the α-chain locus begins to rearrange.
thymic cortical epithelial cells and the receptors of developing T cells has a crucial role in positive selection, as we will see later in this chapter.
After positive selection, developing T cells migrate from the cortex to the medulla. The medulla contains fewer lymphocytes, and those present are predominantly the newly matured single-positive T cells that will eventually leave the thymus. The medulla plays a role in negative selection. The antigen-presenting cells in this environment include dendritic cells that express co-stimulatory molecules, which are generally absent from the cortex. In addition, specialized medullary epithelial cells present peripheral antigens for the negative selection of T cells reactive for these self antigens.
8-15 T cells with α:βor γ:δ receptors arise from a common progenitor.
T cells bearing γ:δ receptors differ from α:β T cells in that they are found primarily in epithelial and mucosal sites and lack expression of the CD4 and CD8 co-receptors; in comparison with α:β T cells, relatively little is known about the ligands recognized by the γ:δ T-cell receptors, which are thought not to be MHC restricted (see Section 4-20). Recall from Section 5-11 that different genetic loci are used to make these two types of T-cell receptors. The γ and δ loci are the first to undergo rearrangement, followed shortly thereafter by the β locus. In addition, the δ locus is contained within the α locus, so rearrangements at the α locus eliminate the δ coding sequences on the chromosome. While the mechanism regulating commitment of individual precursor cells to the α:β versus the γ:δ lineage is still not understood, there is some plasticity in this process. This can be deduced from the pattern of gene rearrangements found in thymocytes and in mature γ:δ and α:β T cells. Mature γ:δ T cells can contain rearranged β-chain genes, although 80% of these are nonproductive, and mature α:β T cells often contain rearranged, but mostly out-of-frame, γ-chain genes.
8-16 T cells expressing γ:δ T-cell receptors arise in two distinct phases during development.