T cell receptor repertoires of mice and humans are clustered in similarity networks around conserved public CDR3 sequences

Abstract

Diversity of T cell receptor (TCR) repertoires, generated by somatic DNA rearrangements, is central to immune system function. However, the level of sequence similarity of TCR repertoires within and between species has not been characterized. Using network analysis of high-throughput TCR sequencing data, we found that abundant CDR3-TCRβ sequences were clustered within networks generated by sequence similarity. We discovered a substantial number of public CDR3-TCRβ segments that were identical in mice and humans. These conserved public sequences were central within TCR sequence-similarity networks. Annotated TCR sequences, previously associated with self-specificities such as autoimmunity and cancer, were linked to network clusters. Mechanistically, CDR3 networks were promoted by MHC-mediated selection, and were reduced following immunization, immune checkpoint blockade or aging. Our findings provide a new view of T cell repertoire organization and physiology, and suggest that the immune system distributes its TCR sequences unevenly, attending to specific foci of reactivity.DOI: http://dx.doi.org/10.7554/eLife.22057.001

A scoring system for the electrostatic complementarities of T‐cell receptors and cancer‐mutant amino acids: multi‐cancer analyses of associated survival rates

“…The above analyses, based on exome recoverable TCRs, and thereby based on TCRs that are likely to be dominant TCRs among the TILs, raise a multitude of questions regarding dominant TCR availability and response of T-cells representing a dominant TCR, especially in persons of older age, where dominant TCRs may be more likely. [31][32][33] For example, such data raise the question of whether the pre-existence of a relatively restricted repertoire of TCRs governs the likelihood of a TCR being available for an electrostatically complementary mutant epitope? Such considerations presuppose the possibility that tumor antigens have either a limited, or even a complete lack of ability to stimulate a de novo T-cell response from any T-cell among the millions imaginable based on a naive repertoire.…”

Two signal half‐century: From negative selection of self‐reactivity to positive selection of near‐self‐reactivity

“…The private TCRs tend to be directed against not‐self (ie, pathogen‐derived) antigens, whereas public TCRs tend to be directed against self‐antigens. The “basic network architecture” so generated is, over time, “modified by immunization and ageing due to the dominant expansion of more private CDR3 clonotypes.”…”

Predicting the spectrum of TCR repertoire sharing with a data‐driven model of recombination

“…13 The advent of high-throughput sequencing of TCR repertoires [14][15][16][17] has largely confirmed this view through the analysis of shared TCR sequences between unrelated humans, [18][19][20] monozygous human twins, 21,22 and mice. 23 However, despite recent efforts to characterize the landscape of public TCRs, 24 the contributions of V(D)J generation biases and convergent recombination relative to convergent selection remain to be elucidated and quantified. Selection effects include thymic selection 25 by which receptors that bind too strongly or too weakly to self peptides are eliminated in the thymus, peripheral tolerance by clonal deletion or conversion, and clonal selection by which receptors proliferate upon recognizing specific antigens in the periphery.…”