FIGURE 8-22 CD4 and CD8 expression on thymocytes and positive selection of T cells in the thymus. A, The maturation of thymocytes can be followed by changes in expression of the CD4 and CD8 coreceptors. A two-color flow cytometric analysis of thymocytes using anti-CD4 and anti-CD8 antibodies, each tagged with a different fluorochrome, is illustrated. The percentages of all thymocytes contributed by each major population are shown in the four quadrants. The least mature subset is the CD4-CD8- (double-negative) cells. Arrows indicate the sequence of maturation. B, Positive selection of T cells. Double-positive T cells differentiate into a CD4+CD8low stage and are instructed to become CD4+ cells if the TCR on a double-positive T cell recognizes self class II MHC with moderate avidity and therefore receives adequate coreceptor signals. A CD4+CD8low T cell whose TCR recognizes MHC class I molecules fails to receive strong coreceptor signals and differentiates into a CD8+ T cell, silencing CD4 expression.
suppress further rearrangement, there is little or no allelic exclusion in the a chain locus. Therefore, productive TCR a rearrangements may occur on both chromosomes, and if this happens, the T cell will express two a chains. In fact, up to 30% of mature peripheral T cells do express two different TCRs, with different a chains but the same p chain. It is possible that only one of the two a chains participates in the formation of the functional antigen-specific TCR. Transcriptional regulation of the a chain gene occurs in a similar manner to that of the p chain. There are promoters 5' of each Va gene that have low-level activity and are responsible for high-level T cell-specific transcription when brought close to an a chain enhancer located 3' of the Ca gene. The inability to successfully rearrange the TCR a chain on either chromosome leads to a failure of positive selection (discussed later). Thymocytes that fail to make a productive rearrangement of the TCR a chain gene will die by apoptosis.
TCR a gene expression in the double-positive stage leads to the formation of the complete ap TCR, which is expressed on the cell surface in association with CD3 and Z proteins. The coordinate expression of CD3 and Z proteins and the assembly of intact TCR complexes are required for surface expression. Rearrangement of the TCR a gene results in deletion of the TCR 8 locus that lies between V segments (common to both a and 8 loci) and Ja segments (see Fig. 8-7). As a result, this T cell is no longer capable of becoming a y8 T cell and is completely committed to the ap T cell lineage. The expression of Rag genes and further TCR gene recombination cease after this stage of maturation.
Double-positive cells that successfully undergo selection processes go on to mature into CD4+ or CD8+ T cells, which are called single-positive thymocytes. Thus, the stages of T cell maturation in the thymus can readily be distinguished by the expression of CD4 and CD8 (Fig. 8-22A). This phenotypic maturation is accompanied by functional maturation. CD4+ cells acquire the ability to produce cytokines in response to subsequent antigen stimulation and to express effector molecules (such as CD40 ligand) that "help" B lymphocytes, dendritic cells, and macrophages, whereas CD8+ cells become capable of producing molecules that kill other cells. Mature single-positive thymocytes enter the thymic medulla and then leave the thymus to populate peripheral lymphoid tissues.
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