The T-cell receptor α-chain genes are comparable to the immunoglobulin κ and λ light-chain genes in that they do not have D gene segments and are rearranged only after their partner receptor chain has been expressed. As with the light-chain genes, repeated attempts at α-chain gene rearrangement are possible, as illustrated in Fig. 8.25. The presence of multiple Vα gene segments, and about 60 Jα gene segments spread over some 80 kilobases of DNA, allows many successive Vα to Jα rearrangements to take place at both α-chain alleles. This means that T cells with an initial nonproductive α-gene rearrangement are much more likely to be rescued by a subsequent rearrangement than are B cells with a nonproductive light-chain gene rearrangement.
One key difference between B and T cells is that the final assembly of an immunoglobulin leads to the cessation of gene rearrangement and initiates the further differentiation of the B cell, whereas rearrangement of the Vα gene segments continues in T cells unless there is signaling by a self peptide:self MHC complex that positively selects the receptor (see Section 8-19 below). This means that many T cells have in-frame rearrangements on both chromosomes and so can produce two types of α chains. This is possible because expression of the T-cell receptor is not in itself sufficient to shut off gene rearrangement. Continued rearrangements on both chromosomes can allow several different α chains to be produced successively as well as simultaneously in each developing T cell and to be tested for self peptide:self MHC recognition in partnership with the same β chain. This phase of gene rearrangement lasts for 3 or 4 days in the mouse and ceases only when positive selection occurs as a consequence of receptor engagement, or when the cell dies. One can predict that if the frequency of positive selection is sufficiently low, roughly one in three mature T cells will express two productively rearranged α chains at the cell surface. This has been confirmed for both human and mouse T cells. Thus, in the strict sense, T-cell receptor α-chain genes are not subject to allelic exclusion.
T cells with dual specificity might be expected to give rise to inappropriate immune responses if the cell is activated through one receptor yet can act upon target cells recognized by the second receptor. However, only one of the two receptors is likely to be able to recognize peptide presented by a self MHC molecule, and so the T cell will have only a single functional specificity. This is because once a thymocyte has been positively selected by self peptide:self MHC recognition, α-chain gene rearrangement ceases. Thus, the existence of cells with two α-chain genes productively rearranged and two α chains expressed at the cell surface does not truly challenge the idea that a single functional specificity is expressed by each cell.
Fig. 8.25 Multiple successive rearrangement events can rescue nonproductive T-cell receptor α-chain gene rearrangements. The multiplicity of V and J gene segments at the α-chain locus allows successive rearrangement events to ‘leapfrog’ over previously rearranged VJ segments, deleting any intervening gene segments. The α-chain rescue pathway resembles that of the immunoglobulin κ light-chain genes (see Section 8-5), but the number of possible successive rearrangements is greater. α-chain gene rearrangement continues until either a productive rearrangement leads to positive selection or the cell dies.
Summary.
The thymus provides a specialized and architecturally organized microenvironment for the development of mature T cells. Precursors of T cells migrate from the bone marrow to the thymus, where they interact with environmental cues, such as ligands for the Notch receptor, that drive commitment to the T lineage. Developing thymocytes develop along one of several T-cell lineages: the most prominent subsets in the thymus are γ:δ T cells, conventional α:β T cells, and α:β T cells with receptors of very limited diversity, such as iNKT cells.