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Original Article |
Correspondence to: Nikos Yannoutsos, The Rockefeller University, Box 220, 1230 York Ave., New York, NY 10021. Tel:212-327-8068 Fax:212-327-8370 E-mail:yannoun{at}mail.rockefeller.edu.
Assembly of T cell receptor (TCR)
/ß genes by variable/diversity/joining (V[D]J) rearrangement is an ordered process beginning with recombination activating gene (RAG) expression and TCRß recombination in CD4-CD8-CD25+ thymocytes. In these cells, TCRß expression leads to clonal expansion, RAG downregulation, and TCRß 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 /ß 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 /ß 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
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