| First Author | Brady BL | Year | 2011 |
| Journal | J Immunol | Volume | 187 |
| Issue | 6 | Pages | 3277-85 |
| PubMed ID | 21844384 | Mgi Jnum | J:179246 |
| Mgi Id | MGI:5301500 | Doi | 10.4049/jimmunol.1101079 |
| Citation | Brady BL, et al. (2011) Differential regulation of proximal and distal Vbeta segments upstream of a functional VDJbeta1 rearrangement upon beta-selection. J Immunol 187(6):3277-85 |
| abstractText | Developmental stage-specific regulation of transcriptional accessibility helps control V(D)J recombination. Vbeta segments on unrearranged TCRbeta alleles are accessible in CD4(-)/CD8(-) (double-negative [DN]) thymocytes, when they recombine, and inaccessible in CD4(+)/CD8(+) (double-positive [DP]) thymocytes, when they do not rearrange. Downregulation of Vbeta accessibility on unrearranged alleles is linked with Lat-dependent beta-selection signals that inhibit Vbeta rearrangement, stimulate Ccnd3-driven proliferation, and promote DN-to-DP differentiation. Transcription and recombination of Vbetas on VDJbeta-rearranged alleles in DN cells has not been studied; Vbetas upstream of functional VDJbeta rearrangements have been found to remain accessible, yet not recombine, in DP cells. To elucidate contributions of beta-selection signals in regulating Vbeta transcription and recombination on VDJbeta-rearranged alleles, we analyzed wild-type, Ccnd3(-/-), and Lat(-/-) mice containing a preassembled functional Vbeta1DJCbeta1 (Vbeta1(NT)) gene. Vbeta10 segments located just upstream of this VDJCbeta1 gene were the predominant germline Vbetas that rearranged in Vbeta1(NT/NT) and Vbeta1(NT/NT)Ccnd3(-/-) thymocytes, whereas Vbeta4 and Vbeta16 segments located further upstream rearranged at similar levels as Vbeta10 in Vbeta1(NT/NT)Lat(-/-) DN cells. We previously showed that Vbeta4 and Vbeta16, but not Vbeta10, are transcribed on Vbeta1(NT) alleles in DP thymocytes; we now demonstrate that Vbeta4, Vbeta16, and Vbeta10 are transcribed at similar levels in Vbeta1(NT/NT)Lat(-/-) DN cells. These observations indicate that suppression of Vbeta rearrangements is not dependent on Ccnd3-driven proliferation, and DN residence can influence the repertoire of Vbetas that recombine on alleles containing an assembled VDJCbeta1 gene. Our findings also reveal that beta-selection can differentially silence rearrangement of germline Vbeta segments located proximal and distal to functional VDJbeta genes. |
