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Original Article

^a Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10021
^b Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021
^c Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
^d Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
The Rockefeller University, Box 220, 1230 York Ave., New York, NY 10021.212-327-8370212-327-8068

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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