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Recombination Signal Sequence-Associated Restriction on TCR Gene Rearrangement Affects the Development of Tissue-Specific T Cells¹

Uzodinma N. Uche,^2* Christopher R. Huber,^* David H. Raulet, and Na Xiong^3*

^*Center for Molecular Immunology and Infectious Diseases, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802; and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720

Assembly of TCR and TCR genes from the TCR/ locus is tightly controlled for the proper generation of β and T cells. Of >100 shared variable gene segments in the TCR/ locus, only a few are predominantly used for the TCR gene assembly, while most are for TCR. However, the importance and mechanisms of the selective variable gene rearrangement for T cell development are not fully understood. We report herein that the development of a tissue-specific T cell population is critically affected by recombination signal sequence-associated restriction on the variable gene usage for TCR assembly. We found that the development of substitute skin T cells in mice deficient of the TCR3 gene, which is used in wild-type skin T cells, was drastically affected by the strain background. A V2⁺ skin T cell population developed in mice of the B6 but not the 129 strain backgrounds, due to a difference in the rearrangement of endogenous V7⁺ TCR genes, which paired with the V2⁺ TCR gene to generate the V2/V7⁺ skin T cell precursors in fetal thymi of the B6 background mice. The defective TCR rearrangement of the 129-"V7" gene was associated with specific variations in its recombination signal sequence, which renders it poorly compatible for rearrangement to D genes. These findings provide the first direct evidence that recombination signal sequence-associated restriction on the variable gene usage for TCR/ gene assembly plays an important role in T cell development.

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 This work was supported by grants from the National Institutes of Health (5R01AI071043 to N.X. and 5R01AI031650 to D.H.R.) and, in part, under a grant with the Pennsylvania Department of Health using Tobacco Settlement Funds (to N.X.). The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions.

² Current address: Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591.

³ Address correspondence and reprint requests to Dr. Na Xiong, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, 115 Henning Building, University Park, PA 16802. E-mail address: nux1{at}psu.edu

⁴ Abbreviations used in this paper: DETC, dendritic epidermal T cell; RSS, recombination signal sequence.

⁵ The online version of this article contains supplemental material.