Ludwig Centre for Cancer Research, University of Lausanne, Epalinges, Switzerland.
EMBO J. 2012 Apr 4;31(7):1666-78. doi: 10.1038/emboj.2012.48. Epub 2012 Feb 28.
Although the T-cell receptor αδ (TCRαδ) locus harbours large libraries of variable (TRAV) and junctional (TRAJ) gene segments, according to previous studies the TCRα chain repertoire is of limited diversity due to restrictions imposed by sequential coordinate TRAV-TRAJ recombinations. By sequencing tens of millions of TCRα chain transcripts from naive mouse CD8(+) T cells, we observed a hugely diverse repertoire, comprising nearly all possible TRAV-TRAJ combinations. Our findings are not compatible with sequential coordinate gene recombination, but rather with a model in which contraction and DNA looping in the TCRαδ locus provide equal access to TRAV and TRAJ gene segments, similarly to that demonstrated for IgH gene recombination. Generation of the observed highly diverse TCRα chain repertoire necessitates deletion of failed attempts by thymic-positive selection and is essential for the formation of highly diverse TCRαβ repertoires, capable of providing good protective immunity.
尽管 T 细胞受体 αδ (TCRαδ) 基因座拥有大量的可变 (TRAV) 和连接 (TRAJ) 基因片段，但根据之前的研究，由于顺序协调的 TRAV-TRAJ 重组所施加的限制，TCRα 链库的多样性有限。通过对幼稚小鼠 CD8(+) T 细胞的数千万个 TCRα 链转录本进行测序，我们观察到一个非常多样化的库，包含几乎所有可能的 TRAV-TRAJ 组合。我们的发现与顺序协调基因重组不兼容，而是与一个模型一致，该模型表明 TCRαδ 基因座中的收缩和 DNA 环化为 TRAV 和 TRAJ 基因片段提供了平等的访问，类似于 IgH 基因重组所证明的那样。观察到的高度多样化 TCRα 链库的产生需要通过胸腺阳性选择删除失败的尝试，对于形成高度多样化的 TCRαβ 库至关重要，能够提供良好的保护性免疫。
