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Developmental Stage-Specific Regulation of TCR--Chain Gene Assembly by Intrinsic Features of the TEA Promoter¹

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

The TCR - and -chain genes lie in a single complex locus, the TCR/ locus. TCR-chain genes are assembled in CD4^–CD8^– (double negative (DN)) thymocytes and TCR-chain genes are assembled in CD4⁺CD8⁺ (double positive) thymocytes due, in part, to the developmental stage-specific activities of the TCR and TCR enhancers (E and E), respectively. E functions with TCR promoters to mediate TCR-chain gene assembly in DN thymocytes. However, E is unable to function with TCR promoters such as the TEA promoter to drive TCR-chain gene assembly in these cells. This is important, because the premature assembly of TCR-chain genes in DN thymocytes would disrupt and T cell development. The basis for TEA inactivity in DN thymocytes is unclear, because E can activate the V5 gene segment promoter that lies only 4 kb upstream of TEA promoter. In this study, we use gene targeting to construct a modified TCR/ locus (TCR/^5T) in which the TEA promoter lies in the same location as the V5 gene segment on the wild-type TCR/ allele. Remarkably, the TEA promoter on this allele exhibits normal developmental stage-specific regulation, being active in double positive thymocytes but not in DN thymocytes as is the case with the V5 promoter. Thus, the inactivity of the TEA promoter in DN thymocytes is due primarily to intrinsic developmental stage-specific features of the promoter itself and not to its location relative to other cis-acting elements in the locus, such as E.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ B.P.S. is supported by National Institutes of Health Grants AI47829 and AI49934 and American Cancer Society Grant RSG-05-070-01-LIB.

² Address correspondence and reprint requests to Dr. Barry P. Sleckman, Department of Pathology and Immunology, 660 South Euclid Avenue, Campus Box 8118, Washington University School of Medicine, St. Louis, MO 63110. E-mail address: Sleckman{at}immunology.wustl.edu

³ Abbreviations used in this paper: DN, double negative; DP, double positive; LMPCR, ligation-mediated PCR; RSS, recombination signal sequence; SE, signal end.