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| The role of recombination activating gene (RAG) reinduction in thymocyte development in vivo |
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| Author(s): Yannoutsos N, Wilson P, Yu W, Chen HT, Nussenzweig A, Petrie H, Nussenzweig MC |
| Source: JOURNAL OF EXPERIMENTAL MEDICINE Volume: 194 Issue: 4 Pages: 471-480 Published: AUG 20 2001 |
| Times Cited: 34 References: 68 |
| Abstract: Assembly of T cell receptor (TCR)alpha/beta genes by variable/diversity/joining (V[D]J) rearrangement is an ordered process beginning with recombination activating gene (RAG) expression and TCR beta recombination in CD4(-)CD8(-)CD25(+) thymocytes. In these cells, TCR beta expression leads to clonal expansion, RAG downregulation, and TCR beta allelic exclusion. At the subsequent CD4(+)CD8(+) stage, RAG expression is reinduced and V(D)J recombination is initiated at the TCR alpha locus. This second wave of RAG expression is terminated upon expression of a positively selected alpha/beta 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 alpha rearrangement is restricted to the 5' end of the J alpha cluster and there is little apparent secondary TCR alpha recombination. Comparison of the TCR alpha genes expressed in wild-type or mutant mice shows that 65% of all alpha/beta T cells carry receptors that are normally assembled by secondary TCR alpha rearrangement. We conclude that RAG reinduction in CD4(+)CD8(+) thymocytes is not required for initial TCR alpha recombination but is essential for secondary TCR alpha recombination and that the majority of TCR alpha chains expressed in mature T cells are products of secondary recombination. |
| Document Type: Article |
| Language: English |
| Reprint Address: Yannoutsos, N (reprint author), Rockefeller Univ, Lab Mol Immunol, Box 220,1230 York Ave, New York, NY 10021 USA |
Addresses:
1. Rockefeller Univ, Lab Mol Immunol, New York, NY 10021 USA
2. Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA
3. Mem Sloan Kettering Canc Ctr, Program Immunol, New York, NY 10021 USA
4. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA |
| Publisher: ROCKEFELLER UNIV PRESS, 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA |
| Subject Category: Immunology; Medicine, Research & Experimental |
| IDS Number: 466DH |
| ISSN: 0022-1007 |
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| | | | | | | | | Record from Web of Science® | | | | | | | | | |