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Assembled DJβ Complexes Influence TCRβ Chain Selection and Peripheral Vβ Repertoire¹

Andrea C. Carpenter^*,, Katherine S. Yang-Iott, Linda H. Chao, Beth Nuskey, Scott Whitlow, Frederick W. Alt and Craig H. Bassing^2,*,

^* Immunology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Abramson Family Cancer Research Institute, Philadelphia, PA 19104; and Howard Hughes Medical Institute, Children’s Hospital, Immune Disease Institute, and Department of Genetics, Harvard University Medical School, Boston, MA 02115

TCRβ chain repertoire of peripheral β T cells is generated through the stepwise assembly and subsequent selection of TCRβ V region exons during thymocyte development. To evaluate the influence of a two-step recombination process on Vβ rearrangement and selection, we generated mice with a preassembled Dβ1Jβ1.1 complex on the Jβ1 allele, an endogenous TCRβ allele that lacks the Dβ2-Jβ2 cluster, creating the Jβ1^DJβ allele. As compared with Jβ1^/ mice, both Jβ1^DJβ/ and Jβ1^DJβ/DJβ mice exhibited grossly normal thymocyte development and TCRβ allelic exclusion. In addition, Vβ rearrangements on Jβ1^DJβ and Jβ1 alleles were similarly regulated by TCRβ-mediated feedback regulation. However, in-frame VβDJβ rearrangements were present at a higher level on the Jβ1^DJβ alleles of Jβ1^DJβ/ β T cell hybridomas, as compared with on the Jβ1 alleles. This bias was most likely due to both an increased frequency of Vβ-to-DJβ rearrangements on Jβ1^DJβ alleles and a preferential selection of cells with in-frame VβDJβ exons assembled on Jβ1^DJβ alleles during the development of Jβ1^DJβ/ β T cells. Consistent with the differential selection of in-frame VβDJβ rearrangements on Jβ1^DJβ alleles, the Vβ repertoire of β T cells was significantly altered during β TCR selection in Jβ1^DJβ/ and Jβ1^DJβ/DJβ mice, as compared with in Jβ1^/ mice. Our data indicate that the diversity of DJβ complexes assembled during thymocyte development influences TCRβ chain selection and peripheral Vβ repertoire.

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 National Institutes of Health Grant AI20047 (to F.W.A.) and the Department of Pathology and Laboratory Medicine and Center for Childhood Cancer Research of the Children’s Hospital of Philadelphia (to C.H.B.). A.C.C. is supported by the Training Program in Immune System Development and Regulation at the University of Pennsylvania. C.H.B. is a Pew Scholar in the Biomedical Sciences. F.W.A. is an Investigator of the Howard Hughes Medical Institute.

² Address correspondence and reprint requests to Dr. Craig H. Bassing, Children’s Hospital of Philadelphia, 807A Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, PA 19104. E-mail address: bassing{at}email.chop.edu

³ Abbreviations used in this paper: RSS, recombination signal sequence; DN, double negative; DP, double positive; ES, embryonic stem; ETP, early T lineage progenitor; NHEJ, nonhomologous end joining; SA, streptavidin; SP, single positive.