FIGURE 8-20 Maturation of T cells in the thymus. Precursors of T cells travel from the bone marrow through the blood to the thymus. In the thymic cortex, progenitors of aP T cells express TCRs and CD4 and CD8 coreceptors. Selection processes eliminate self-reactive T cells in the cortex at the double-positive (DP) stage and also single-positive (SP) medullary thymocytes. They promote survival of thymocytes whose TCRs bind self MHC molecules with low affinity. Functional and phenotypic differentiation into CD4+CD8- or CD8+CD4- T cells occurs in the medulla, and mature T cells are released into the circulation.
protein. The two Cp genes appear to be functionally interchangeable, and there is no evidence that an individual T cell ever switches from one C gene to another. Furthermore, the use of either Cp gene segment does not influence the function or specificity of the TCR. The promoters in the 5' flanking regions of Vp genes function together with a powerful enhancer that is located 3' of the Cp2 gene once V genes are brought close to the C gene by VDJ recombination. This proximity of the promoter to the enhancer is responsible for high-level T cell-specific transcription of the rearranged TCR P chain gene.
If a productive (i.e., in-frame) rearrangement of the TCR p chain gene occurs in a given pro-T cell, the TCR p chain protein is expressed on the cell surface in association with an invariant protein called pre-Ta and with CD3 and Z proteins to form the pre-T cell receptor (pre-TCR) (see Fig. 8-16B). The pre-TCR mediates the selection of the developing pre-T cells that productively rearrange the P chain of the TCR. Roughly half of all developing pre-T cells add or remove bases at rearrangement junctions that are multiples of three (on at least one TCR P chromosome), and therefore approximately half of all developing pre-T cells fail to express a TCR P protein. The function of the pre-TCR complex in T cell development is similar to that of the surrogate light chain-containing pre-BCR in B cell development. Signals from the pre-TCR mediate the survival of pre-T cells and contribute to the largest proliferative expansion during T cell development. Pre-TCR signals also initiate recombination at the TCR a chain locus and drive the transition from the double-negative to the double-positive stage of thymocyte development (discussed later). These signals also inhibit further rearrangement of the TCR P chain locus largely by limiting accessibility of the other allele to the recombination machinery. This results in P chain allelic exclusion (i.e., mature T cells express only one of the two inherited P chain alleles). As in pre-B cells, it is not known what, if any, ligand the pre-TCR recognizes. Pre-TCR signaling, like pre-BCR signaling, is generally believed to be initiated in a ligand-independent manner, dependent on the successful assembly of the pre-TCR complex. Pre-TCR signaling is mediated by a number of cytosolic kinases and adaptor proteins that are known also to be linked to TCR signaling (see Chapter 7). The essential function of the pre-TCR in T cell maturation has been demonstrated by numerous studies with genetically mutated mice, in which lack of any component of the pre-TCR complex (i.e., the TCR P chain, pre-Ta, CD3, Z, or Lck) results in a block in the maturation of T cells at the double-negative stage.
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