During T cell maturation, there is a precise order in which TCR genes are rearranged and in which the TCR and CD4 and CD8 coreceptors are expressed (Fig. 8-20; see also Fig. 8-19). In the mouse, surface expression of the y8 TCR occurs first, 3 to 4 days after precursor cells first arrive in the thymus, and the ap TCR is expressed 2 or 3 days later. In human fetal thymuses, y8 TCR expression begins at about 9 weeks of gestation, followed by expression of the ap TCR at 10 weeks.
The most immature cortical thymocytes, which are recent arrivals from the bone marrow, contain TCR genes in their germline configuration and do not express TCR, CD3, Z chains, CD4, or CD8; these cells are called doublenegative thymocytes. Thymocytes at this stage are also considered to be at the pro-T cell stage of maturation. The majority (>90%) of the double-negative thymocytes that survive thymic selection processes will ultimately give rise to ap TCR-expressing, MHC-restricted CD4+ and CD8+ T cells, and the remainder of these thymocytes will give rise to y8 T cells. Rag-1 and Rag-2 proteins are first expressed at the pro-T stage of development and are required for the rearrangement of TCR genes. Dp-to-Jp rearrangements at the TCR p chain locus occur first; these involve either joining of the Dp1 gene segment to one of the six Jp1 segments or joining of the Dp2 segment to one of the six Jp2 segments (Fig. 8-21A). Vp-to-DJp rearrangements occur at the transition between the pro-T stage and the subsequent pre-T stage during ap T cell development. The DNA sequences between the segments undergoing rearrangement, including D, J, and possibly Cp1 genes (if Dp2 and Jp2 segments are used), are deleted during this rearrangement process. The primary nuclear transcripts of the TCR p genes contain the intron between the recombined VDJp exon and the relevant Cp gene. Poly-A tails are added after cleavage of the primary transcript downstream of consensus polyadenylation sites located 3' of the Cp region, and the sequences between the VDJ exon and Cp are spliced out to form a mature mRNA in which VDJ segments are juxtaposed to either of the two Cp genes (depending on which J segment was selected during the rearrangement process). Translation of this mRNA gives rise to a full-length TCR p chain
Bone marrow Thymus PeriPhery fetal liver Cortex Medulla PeriPhery
Death by neglect (no or low affinity)
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