TCR repertoire: size, diversity, and function

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Thymic regulatory T cells (tTreg) are critical in maintenance of normal T cell immunity and tolerance. The role of TCR in tTreg cell selection remains incompletely understood. Here we assessed TCR and TCR sequences of mouse tTreg and conventional thymic CD4+ T (Tconv) cells by high throughput sequencing. We identified TCR sequences that were unique to either tTreg or Tconv cells and found that these were distinct as recognized by machine learning (ML) algorithm and by preferentially used amino acid trimers in CDR3 of tTreg cells. In addition, a proportion of TCR sequences expressed by tTreg were also found in Tconv cells, and ML classified the great majority of these shared TCR sequences as characteristic of Tconv and not tTreg cells. These findings identify two populations of tTreg, one in which Treg fate is associated with unique properties of the TCR, and another with TCR properties characteristic of Tconv cells for which tTreg fate is determined by factors beyond TCR sequence. A diverse TCR repertoire is considered essential for T cell immunity to provide protection of the host against all potential pathogens. However, the size and content of the TCR repertoire and its changes with age remains elusive. Here, we report a longitudinal analysis of TCR repertoire of human CD4+ and CD8+ T cells and nave and memory subsets from 30 healthy adults aged from 25 to 85 at first visit and an average of 9-year follow-up as second visit by RNAseq. Through analysis of combined 1.9 x 108 CD4+ and CD8+ T cells, we identified a total of 1.1 x 106 and 2.8 x 106 unique TCR and TCR sequences, respectively. We predicted that an adult has TCR repertoire richness of 4 x 108. TCR repertoire changes estimated by the actual number of circulating T cells displayed the following key age-associated changes: 1) reduction of TCR and TCR repertoire richness in both CD4+ and CD8+ T cells, with the greatest reduction in nave CD8+ T cells; 2) increased clonal expansion of TCR repertoire in all T cell subsets, with the greatest expansion in memory CD8+ T cells; 3) profoundly reduced content changes of CD4+ and CD8+ TCR repertoire, as retention of TCR and TCR sequences increased between two visits, with memory CD8+ T cells showing the highest; and 4) decreased distinction of TCR and TCR sequences between nave and memory T cells, as well as between CD4+ and CD8+ T cells. These findings predicted the size of TCR repertoire in human and described the precise alterations of TCR repertoire in CD4+ and CD8+ T cells and their subsets with age. Collectively, our results suggested that age-related decline of T cell immunity is more severe in CD8+ T cell mediated cytotoxicity than in CD4+ T helper function.