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Distinct Control of the Frequency and Allelic Exclusion of the V Gene Rearrangement at the TCR Locus¹

Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139

Ag receptor gene loci contain many V gene segments, each of which is recombined and expressed at a different frequency and is subject to allelic exclusion. To probe the parameters that mediate the different levels of regulation of V gene rearrangement, a V gene segment together with 3.6-kb 5' and 0.7-kb 3' flanking sequences was inserted 6.8 kb upstream of the D1 gene segment in the murine TCR locus. Despite its proximity to the D gene segments and the E enhancer, the inserted V segment underwent VDJ recombination at the same frequency as the natural copy located 470 kb upstream. However, the inserted V segment was no longer under allelic exclusion control as it recombined at a similar frequency in the presence of a TCR transgene. These results suggest that while the inserted fragment contains the necessary cis-regulatory elements for determining the frequency of V rearrangement, additional cis-regulatory elements are required for mediating V allelic exclusion. Interestingly, most of the inserted V rearrangements were not transcribed and expressed in the presence of a TCR transgene, suggesting that TCR allelic exclusion can also be achieved by blocking the transcription of the rearranged gene segments. These findings provide strong evidence for distinct control of the frequency and allelic exclusion of V gene rearrangement.

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