Convergent recombination shapes the clonotypic landscape of the naïve T-cell repertoire

Abstract

Adaptive T-cell immunity relies on the recruitment of antigenspecific clonotypes, each defined by the expression of a distinct T-cell receptor (TCR), from an array of naïve T-cell precursors. Despite the enormous clonotypic diversity that resides within the naïve T-cell pool, interindividual sharing of TCR sequences has been observed within mobilized T-cell responses specific for certain peptide-major histocompatibility complex (pMHC) antigens. The mechanisms that underlie this phenomenon have not been fully elucidated, however. A mechanism of convergent recombination has been proposed to account for the occurrence of shared, or "public," TCRs in specific memory T-cell populations. According to this model, TCR sharing between individuals is directly related to TCR production frequency; this, in turn, is determined on a probabilistic basis by the relative generation efficiency of particular nucleotide and amino acid sequences during the recombination process. Here, we tested the key predictions of convergent recombination in a comprehensive evaluation of the naïve CD8 + TCRβ repertoire in mice. Within defined segments of the naïve CD8 + T-cell repertoire, TCRβ sequences with convergent features were (i) present at higher copy numbers within individual mice and (ii) shared between individual mice. Thus, the naïve CD8 + T-cell repertoire is not flat, but comprises a hierarchy of recurrence rates for individual clonotypes that is determined by relative production frequencies. These findings provide a framework for understanding the early mobilization of public CD8 + T-cell clonotypes, which can exert profound biological effects during acute infectious processes.

Determinants of public T cell responses

“…The analysis of pre-selection DP thymocytes from this mouse showed a diverse array of TCR CDR3 α sequences, while thymic selection produced a post-selection repertoire with marked overrepresentation of a subset of sequences, indicating that DP cells expressing particular CDR3 α sequences might have quite different probabilities of being selected [59]. But this suggestion is challenged by the facts that the sequencing information of these studies is not sufficient to observe the true extent of clonotypic frequency differences within the pre-selection repertoire [32], and that the hierarchy of clonotypic frequency is preserved during intra-thymic development (see discussion above).…”

“…Furthermore, there are TCR sequences that are most likely to be produced during random convergent recombination, but are present at lower clonotype frequencies and only shared by fewer individuals [32,[38][39][40] (and our unpublished data), indicating preferences during recombination. Indeed, biases during recombination have been reported by many studies.…”

“…Furthermore, V β -J β combination usage by TCR β functional nucleotide sequences in human naïve repertoire was similar to that of nonfunctional TCR β nucleotide sequences [33], and β-chains were positively selected with similar efficiency regardless of CDR3 loop sequences [64]. Considering the effects of convergent recombination in shaping the intraindividual clonotypic landscape of TCR β  sequences in the naïve repertoire (as discussed above) [32], it seems very likely that initial recombination patterns are preserved during intra-thymic development with no preferential selection for particular TCR sequences and thus thymic selection (convergent evolution) unlikely contributes much to the inter-individual overalp of naïve TCR repertoire.…”

“…Indeed, a large degree of overlap has been observed between the naïve TCR repertoires in inbred mice [31,32] and humans [33,34]. This phenomenon of TCR sharing within the naïve T-cell pool of multiple individuals provides the molecular basis for public T cell responses, enabling epitope-specific clonotype selection based on optimal TCR recognition operating on a partially common platform [35][36][37].…”

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

“…It was proposed7, 8, 9 that these shared sequences can be explained by the biases inherent in the V(D)J recombination process, together with “convergent recombination,” the possibility to generate the same TCR sequence (especially the same CDR3 amino acid sequence) in independent recombination events. 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.…”