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Genetic Modulation of T Cell Receptor Gene Segment Usage during Somatic Recombination

Correspondence to: Howard T. Petrie, Memorial Sloan-Kettering Cancer Center, Box 341, 1275 York Ave., New York, NY 10021. Tel:212-639-2149 Fax:212-794-4019

Lymphocyte antigen receptors are not encoded by germline genes, but rather are produced by combinatorial joining between clusters of gene segments in somatic cells. Within a given cluster, gene segment usage during recombination is thought to be largely random, with biased representation in mature T lymphocytes resulting from protein-mediated selection of a subset of the total repertoire. Here we show that T cell receptor Dß and Jß gene segment usage is not random, but is patterned at the time of recombination. The hierarchy of gene segment usage is independent of gene segment proximity, but rather is influenced by the ability of the flanking recombination signal sequences (RSS) to bind the recombinase and/or to form a paired synaptic complex. Importantly, the relative frequency of gene segment usage established during recombination is very similar to that found after protein-mediated selection, suggesting that in addition to targeting recombinase activity, the RSS may have evolved to bias the naive repertoire in favor of useful gene products.

Key Words: thymus, VDJ recombination, recombination signal sequence, T cell receptor ß locus, repertoire selection

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