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Original Article |
yannoun{at}mail.rockefeller.edu
Assembly of T cell receptor (TCR)
/β genes by variable/diversity/joining (V[D]J) rearrangement is an ordered process beginning with recombination activating gene (RAG) expression and TCRβ recombination in CD4–CD8–CD25+ thymocytes. In these cells, TCRβ expression leads to clonal expansion, RAG downregulation, and TCRβ allelic exclusion. At the subsequent CD4+CD8+ stage, RAG expression is reinduced and V(D)J recombination is initiated at the TCR
locus. This second wave of RAG expression is terminated upon expression of a positively selected
/β TCR. To examine the physiologic role of the second wave of RAG expression, we analyzed mice that cannot reinduce RAG expression in CD4+CD8+ T cells because the transgenic locus that directs RAG1 and RAG2 expression in these mice is missing a distal regulatory element essential for reinduction. In the absence of RAG reinduction we find normal numbers of CD4+CD8+ cells but a 50–70% reduction in the number of mature CD4+CD8– and CD4–CD8+ thymocytes. TCR
rearrangement is restricted to the 5' end of the J
cluster and there is little apparent secondary TCR
recombination. Comparison of the TCR
genes expressed in wild-type or mutant mice shows that 65% of all
/β T cells carry receptors that are normally assembled by secondary TCR
rearrangement. We conclude that RAG reinduction in CD4+CD8+ thymocytes is not required for initial TCR
recombination but is essential for secondary TCR
recombination and that the majority of TCR
chains expressed in mature T cells are products of secondary recombination.
Key Words: T cell receptor
chain gene rearrangement regulation of gene expression T cell receptor editing recombination activating gene
Abbreviations used in this paper: APC, allophycocyanin; BAC, bacterial artificial chromosome; DN, double negative; DP, double positive; NBS, Nijmegen breakage syndrome; SP, single positive; RAG, recombination activating gene; RT, reverse transcription; TEA, T early
promoter; YAC, yeast artificial chromosome. © 2001 The Rockefeller University Press
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