We now return to the development of α:β T cells. The rearrangement of the βand α-chain loci closely parallels the rearrangement of immunoglobulin heavy-chain and light-chain loci during B-cell development (see Sections 8-2 through 8-5). As shown in Fig. 8.24, the β-chain gene segments rearrange first, with the Dβ gene segments rearranging to Jβ gene segments, and this is followed by Vβ to DJβ rearrangement. If no functional β chain can be synthesized from this rearrangement, the cell will not be able to produce a pre-T-cell receptor and will die. However, unlike B cells with nonproductive heavy-chain gene rearrangements, thymocytes with nonproductive β-chain VDJ rearrangements can be rescued by further rearrangement, which is possible because of the two clusters of Dβ and Jβ gene segments upstream of two Cβ genes (see Fig. 5.13).
The likelihood of a productive VDJ join at the β locus is therefore somewhat higher than the 55% chance for a productive immunoglobulin heavy-chain gene arrangement.
Once a productive β-chain gene rearrangement has occurred, the β chain is expressed together with the invariant pTα and the CD3 molecules (see Fig. 8.24) and is transported in this complex to the cell surface. The β:pTα complex is a functional pre-T-cell receptor analogous to the μ:VpreB:λ5 pre-Bcell receptor complex in B-cell development (see Section 8-3). Expression of
Fig. 8.24 The stages of gene rearrangement in α:β T cells. The sequence of gene rearrangements is shown, together with an indication of the stage at which the events take place and the nature of the cell-surface receptor molecules expressed at each stage. The β-chain locus rearranges first, in CD4–CD8– double-negative thymocytes expressing CD25 and low levels of CD44. As with immunoglobulin heavy-chain genes, D to J gene segments rearrange before V gene segments rearrange to DJ (second and third panels). It is possible to make up to four attempts to generate a productive rearrangement at the β-chain locus, because there are four D gene segments with two sets of J gene segments associated with each TCRβ chain locus (not shown). The productively rearranged gene is expressed initially within the cell and then at low levels on the cell surface. It associates with pTα, a surrogate 33-kDa α chain that is equivalent to λ5 in B-cell development, and this pTα:β heterodimer forms a complex with the CD3 chains (fourth panel). The expression of the pre-T-cell receptor signals the developing thymocytes to halt β-chain gene rearrangement and to undergo multiple cycles of division. At the end of this proliferative burst, the CD4 and CD8 molecules are expressed, the cell ceases cycling, and the α chain is now able to undergo rearrangement. The first α-chain gene rearrangement deletes all δ D, J, and C gene segments on the chromosome, although these are retained as a circular DNA, indicating that these are nondividing cells (bottom panel). This permanently inactivates the δ-chain gene. Rearrangements at the α-chain locus can proceed through several cycles, because of the large number of Vα and Jα gene segments, so that productive rearrangements almost always occur.
When a functional α chain is produced that pairs efficiently with the β chain, the CD3lowCD4+CD8+ thymocyte is ready to undergo selection for its ability to recognize self peptides in association with self-MHC molecules.