title: Vbeta cluster sequences reduce the frequency of primary Vbeta2 and Vbeta14 rearrangements.
abstract: T-cell receptor (TCR) beta variable region exons are assembled from numerous gene segments in a highly ordered and regulated manner. To elucidate mechanisms and identify cis-acting elements that control Vbeta rearrangement, we generated an endogenous TCR-beta allele with only the Vbeta2, Vbeta4, and Vbeta14 segments. We found that alphabeta T lineage cells containing this Vbeta(2-4-14) allele and a wild-type TCR-beta allele developed normally, but exhibited a significant increase in Vbeta2(+) and Vbeta14(+) cells. To quantify Vbeta rearrangements on the Vbeta(2-4-14) allele, we generated alphabeta T-cell hybridomas and analyzed TCR-beta rearrangements. Despite the deletion of almost all Vbeta segments and 234 kb of Vbeta cluster sequences, the Vbeta(2-4-14) allele exhibited only a slight decrease in Vbeta rearrangement as compared with the wild-type TCR-beta allele. Thus, cis-acting control elements essential for directing Vbeta rearrangement across large chromosomal distances are not located within the Vbeta cluster. We also found a significant increase in the frequency of Vbeta rearrangements involving Vbeta2 and Vbeta14, but not Vbeta4, on the Vbeta(2-4-14) allele. Collectively, our data suggest that Vbeta cluster sequences reduce the frequency of Vbeta2 and Vbeta14 rearrangements by competing with the productive coupling of accessible Vbeta2 and Vbeta14 segments with DJbeta1 complexes.
authors.affiliation: Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. bassing@email.chop.edu
authors.forename: Craig H
authors.initials: CH
authors.lastname: Bassing
authors.forename: Scott
authors.initials: S
authors.lastname: Whitlow
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslovasky
authors.forename: Katherine
authors.initials: K
authors.lastname: Yang-Iott
authors.forename: Sheila
authors.initials: S
authors.lastname: Ranganath
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
mesh_terms: D000483:Alleles; D000818:Animals; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D019674:Genes, T-Cell Receptor beta; D051379:Mice; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta
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