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Increase of TCR V Accessibility within E Regulatory Region Influences its Recombination Frequency But Not Allelic Exclusion

Makoto Senoo^1,*, Lili Wang^*, Daisuke Suzuki^*, Naoki Takeda, Yoichi Shinkai and Sonoko Habu^2,*

^* Department of Immunology, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan; and Department of Cell Biology, Institute for Virus Research, Kyoto University, Kyoto, Japan

Seventy percent of the murine TCR locus (475 kb) was deleted to generate a large deleted TCR (^LD) allele to investigate a possible linkage between germline transcription, recombination frequency, and allelic exclusion of the TCR V genes. In these ^LD/LD mice, the TCR gene locus contained only four V genes at the 5' side of the locus, and consequently, the V10 gene was located in the original D1-J1cluster within the E regulatory region. We showed that the frequency of recombination and expression of the V genes are strongly biased to V10 in these mutant mice even though the proximity of the other three 5'V genes was also greatly shortened toward the D-J cluster and the E enhancer. Accordingly, the germline transcription of the V10 gene in ^LD/LD mice was exceptionally enhanced in immature double negative thymocytes compared with that in wild-type mice. During double negative-to-double positive transition of thymocytes, the level of V10 germline transcription was prominently increased in ^LD/LD recombination activating gene 2-deficient mice receiving anti-CD3 Ab in vivo. Interestingly, however, despite the increased accessibility of the V10 gene in terms of transcription, allelic exclusion of this V gene was strictly maintained in ^LD/LD mice. These results provide strong evidence that increase of V accessibility influences frequency but not allelic exclusion of the TCR V rearrangement if the V gene is located in the E regulatory region.

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