Age-related changes in the human T cell receptor alpha repertoire suggest positive selection of dual-specific T cells

The human T cell receptor (TCR) repertoire is generated in the thymus through a process of recombination involving two gene loci, TRA and TRB, and the pairing of the resulting peptide chains. Because of the lack of allelic exclusion in TRA loci, it is possible for a T cell to express either one or two distinct TRA chains, and although both configurations are present in significant quantities in the mature T-cell population, this has been viewed a largely inconsequential phenomenon. We analyzed human TRA repertoires using sequencing of genomic DNA as starting material from T-cell subsets representing different maturation stages of T cells, from donors aged from 7 d to 61 yr, some with chronic exposure to pathogen or autoimmune antigens. The frequency of productive TRA clonotypes increased along the T cell maturation stage and showed a consistent positive correlation with the donor age. Moreover, our data provide evidence of chronic antigen exposure further increasing the frequency of productive TRA sequences. We propose that these unexpected findings are due to a preferred positive peripheral selection of the T cell population bearing 2 functional TRA chains.