Persisting fetal clonotypes influence the structure and overlap of adult human T cell receptor repertoires

Abstract

The diversity of T-cell receptors recognizing foreign pathogens is generated through a highly stochastic recombination process, making the independent production of the same sequence rare. Yet unrelated individuals do share receptors, which together constitute a “public” repertoire of abundant clonotypes. The TCR repertoire is initially formed prenatally, when the enzyme inserting random nucleotides is downregulated, producing a limited diversity subset. By statistically analyzing deep sequencing T-cell repertoire data from twins, unrelated individuals of various ages, and cord blood, we show that T-cell clones generated before birth persist and maintain high abundances in adult organisms for decades, slowly decaying with age. Our results suggest that large, low-diversity public clones are created during pre-natal life, and survive over long periods, providing the basis of the public repertoire.

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

“…We find that the distribution of generation probabilities of all TCRβ CDR3 amino acid sequences (Figure 5, blue curves) is extremely broad, spanning many orders of magnitude. This observation is consistent with similar analyses at the level of nucleotide sequences in non‐productive26 and productive20 human TCRβ, in the α and β chains of monozygous twins,22 and mice 28. If we plot instead the generative probability distribution of sequences that are shared among two or more individuals in our dataset, we find that the distribution narrows and shifts toward higher generation probabilities20, 22, 26 as expected.…”

“…Due to their publicness, it had been conjectured that some of these common TCRs might have a close to innate function 31. In this context, it should be noted that young, prebirth repertoires are known to be much less diverse both in humans22 and mice,28 due the late appearance of TdT, the enzyme responsible for insertions in the recombination process. Consequently, the prebirth repertoire is expected to be much more public that the adult one, and could be enriched in innate‐like TCRs.…”

“…The α chain, as part of the αβ receptor, contributes to antigen recognition. It is less diverse than the β chain, implying higher sharing numbers 22. Paired αβ data is becoming available as paired sequencing technologies improve,60, 61 but the resulting repertoires are currently too small or not yet available for analysis.…”

“…Given the probability distributions for the choice of gene segments, deletion profiles and insertion patterns, one can generate in silico TCR repertoire samples that mimic the statistics of real repertoires, and allow us to predict sharing statistics and the effects of convergent recombination 11, 20, 22, 23, 26, 38. To obtain accurate predictions, the distributions of recombination events used in the model must closely match repertoire data.…”

“…In this hypothesis, shared TCRs are simply those that have a higher‐than‐average generation probability and are thus more abundant in the unselected repertoire 13. The advent of high‐throughput sequencing of TCR repertoires14, 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.…”