TCR repertoire: size, diversity, and function

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Understanding how the size and content of TCR reprotire and their changes with age remains a critical challenge in immunobiology. Here, we report a longitudinal analysis of TCR repertoire of human T cells and 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. From analysis of combined 2.0 x 108 nave and memory CD4+ and CD8+ T cells, we identified 1.1 x 106 and 2.8 x 106 unique TCR and TCR sequences. We found despite a general reduction of nave TCR repertoire size with age, the in vivo change of nave TCR repertoire (species richness and D50 index) in the study subjects was highly individualized. Reduction of nave CD4+ and CD8+ TCR repertoires occurred at all adult age from 30-90 but altered expansion of naive CD8+ T cells found in later years, probably due to cumulated unbalanced homeostatic expansion over the years of life. A striking age change is increased similarity of TCR repertoire between nave and memory CD4+ and CD8+ T cells, suggesting nave TCR repertoires may be also selected. These findings provide a framework of TCR and TCR diversity and their changes with age in CD4+ and CD8+ nave and memory T cells. 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 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.