The Journal of Experimental Medicine
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Published online March 31, 2008
doi:10.1084/jem.20071275
The Journal of Experimental Medicine, Vol. 205, No. 4, 929-938
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Xiong et al.
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ARTICLE

 Gene placement and competition control T cell receptor {gamma} variable region gene rearrangement

Na Xiong, Li Zhang, Chulho Kang, and David H. Raulet

Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, Berkeley, CA 94720

CORRESPONDENCE David H. Raulet: Raulet{at}berkeley.edu

The production of distinct sets of T cell receptor (TCR) {gamma}{delta}+ T cells occurs in an ordered fashion in thymic development. The V{gamma}3 and V{gamma}4 genes, located downstream in the TCR{gamma} C{gamma}1 gene cluster, are expressed by the earliest waves of developing TCR{gamma}{delta}+ T cells in the fetal thymus, destined for intraepithelial locations. Upstream V{gamma}2 and V{gamma}5 genes are expressed in later waves in the adult and constitute most TCR{gamma}{delta}+ T cells in secondary lymphoid tissue. This developmental pattern is caused in part by a preference for rearrangements of the downstream V{gamma}3 and V{gamma}4 genes in the early fetal stage, which switches to a preference for rearrangements of the upstream V{gamma}2 and V{gamma}5 gene rearrangements in the adult. Our gene targeting studies show that the downstream V{gamma} genes rearrange preferentially in the early fetal thymus because of their downstream location, independent of promoter or recombination signal sequences and unrelated to the extent of germline transcription. Remarkably, gene deletion studies show that the downstream V{gamma} genes competitively inhibit upstream V{gamma} rearrangements at the fetal stage. These data provide a mechanism for specialization of the fetal thymus for the production of T cells expressing specific V{gamma} genes.

Abbreviations used: DETC, dendritic epidermal T cell; E, embryonic day; ES, embryonic stem; KI, knock-in; RSS, recombination signal sequence(s); TdT, terminal deoxynucleotidyl transferase.

N. Xiong's present address is Dept. of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802.


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