Highly diverse TCRα chain repertoire of pre-immune CD8+ T cells reveals new insights in gene recombination

Although the T-cell receptor alpha delta (TCR alpha delta) locus harbours large libraries of variable (TRAV) and junctional (TRAJ) gene segments, according to previous studies the TCR alpha chain repertoire is of limited diversity due to restrictions imposed by sequential coordinate TRAV-TRAJ recombinations. By sequencing tens of millions of TCR alpha 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 TCR alpha delta locus provide equal access to TRAV and TRAJ gene segments, similarly to that demonstrated for IgH gene recombination. Generation of the observed highly diverse TCR alpha chain repertoire necessitates deletion of failed attempts by thymic-positive selection and is essential for the formation of highly diverse TCR alpha beta repertoires, capable of providing good protective immunity. The EMBO Journal (2012) 31, 1666-1678. doi: 10.1038/emboj.2012.48; Published online 28 February 2012