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Beyond the 12/23 Rule of VDJ Recombination Independent of the Rag Proteins ¹

Alexandru Olaru^*, Howard T. Petrie and Ferenc Livák^2,*,

^* Department of Microbiology and Immunology, Graduate Program in Molecular and Cellular Biology, University of Maryland School of Medicine, Baltimore, MD 21201; and Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL 33101

The combinatorial repertoire of AgRs is established through somatic recombination of V, D, and J gene segments during lymphocyte development. Incorporation of D segments into IgH, TCR, and TCR chains also contributes to junctional diversification by substantially extending the length of the third CDR. The V, D, and J gene segments are flanked by recombination signals (RS) of 12- or 23-mer spacer length that direct recombination according to the 12/23 rule. D genes in the TCR and TCR loci are flanked by a 12RS and 23RS, and their incorporation is controlled by mechanisms "beyond the 12/23 rule." In the TCR locus, selective interactions between Rag proteins and the RS flanking the V-D and D-J genes, respectively, are sufficient to enforce D gene usage. In this article, we report that in the TCR locus, the Rag proteins are not the major determinant of D gene incorporation. In developing mouse and human thymocytes, the two D genes rearrange predominantly to form D-D coding joints. In contrast, when tested in ex vivo transfection assays in a nonlymphoid cell line, the flanking RS mediate deletion, rather than incorporation, of the two D genes on both exogenous recombination substrates and the endogenous locus. These results suggest that selective Rag-RS interactions are not the sole regulators of D gene segment incorporation, and additional, perhaps lymphocyte-specific, mechanisms exist that allow proper shaping of the primary AgR repertoire.