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

Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 10/2010; 107(45):19414-9. DOI: 10.1073/pnas.1010586107
Source: PubMed

ABSTRACT Adaptive T-cell immunity relies on the recruitment of antigen-specific 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.

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Available from: Miles P Davenport, Aug 01, 2014
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    • "Public sequences have a very high level of convergent recombination Previous studies reported that public TCRs manifest a higher level of convergent recombination (Venturi et al. 2006, 2011; Quigley et al. 2010; Li et al. 2012). Our analysis of a large number of individuals revealed a continuous trend; increased sharing was associated with a gradual increase in the mean degree of convergent recombination (Fig. 2A); private CDR3 aa sequences were encoded on average by one nt sequence, the public sequences were encoded by 34.5 nt sequences on average. "
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    ABSTRACT: The T cell receptor (TCR) repertoire is formed by random recombinations of genomic precursor elements; the resulting combinatorial diversity renders unlikely extensive TCR sharing between individuals. Here, we studied CDR3β amino-acid sequence sharing in a repertoire-wide manner, using high-throughput TCR-seq in 28 healthy mice. We uncovered hundreds of public sequences shared by most mice. Public CDR3 sequences, relative to private sequences, are two orders of magnitude more abundant on average, express restricted V/J segments, and feature high convergent nucleic-acid recombination. Functionally, public sequences are enriched for MHC-diverse CDR3 sequences that were previously associated with autoimmune, allograft and tumor-related reactions, but not with anti-pathogen-related reactions. Public CDR3 sequences are shared between mice of different MHC haplotypes, but are associated with different, MHC-dependent, V genes. Thus, despite their random generation process, TCR repertoires express a degree of uniformity in their post-genomic organization. These results, together with numerical simulations of TCR genomic rearrangements, suggest that biases and convergence in TCR recombination combine with ongoing selection to generate a restricted subset of self-associated, public CDR3 TCR sequences, and invite reexamination of the basic mechanisms of T-cell repertoire formation.
    Genome Research 07/2014; DOI:10.1101/gr.170753.113 · 13.85 Impact Factor
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    • "acid multiple sequence alignment . We observed that the center of the TRBD is more conserved than the flanking regions . This could be explained by nucleotide nibbling ( Murphy et al . 2007 ) , though the bias for calling TRBD gene segments cannot be fully ruled out . Regardless , this is consistent with previous reports ( Freeman et al . , 2009 ; Quigley et al . , 2010 ) ."
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    ABSTRACT: The characterization of the human T-cell receptor (TCR) repertoire has made remarkable progress, with most of the work focusing on the TCRβ chains. Here, we analyzed the diversity and complexity of both the TCRα and TCRβ repertoires of three healthy donors. We found that the diversity of the TCRα repertoire is higher than that of the TCRβ repertoire, whereas the usages of the V and J genes tended to be preferential with similar TRAV and TRAJ patterns in all three donors. The V-J pairings, like the V and J gene usages, were slightly preferential. We also found that the TRDV1 gene rearranges with the majority of TRAJ genes, suggesting that TRDV1 is a shared TRAV/DV gene (TRAV42/DV1). Moreover, we uncovered the presence of tandem TRBD (TRB D gene) usage in ~2% of the productive human TCRβ CDR3 sequences. Electronic supplementary material The online version of this article (doi:10.1007/s13238-014-0060-1) contains supplementary material, which is available to authorized users.
    Protein & Cell 05/2014; 5(8). DOI:10.1007/s13238-014-0060-1 · 2.85 Impact Factor
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    • "quences make up a " public " repertoire common to many individuals, formed through convergent evolution or a common source. However, it is also possible that these common sequences are just statistically more frequent, and are likely to be randomly recombined in two individuals independently, as previously discussed by Venturi et al. [6] [7] [21]. In other words, public sequences could just be chance events. "
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    ABSTRACT: The efficient recognition of pathogens by the adaptive immune system relies on the diversity of receptors displayed at the surface of immune cells. T-cell receptor diversity results from an initial random DNA editing process, called VDJ recombination, followed by functional selection of cells according to the interaction of their surface receptors with self and foreign antigenic peptides. To quantify the effect of selection on the highly variable elements of the receptor, we apply a probabilistic maximum likelihood approach to the analysis of high-throughput sequence data from the $\beta$-chain of human T-cell receptors. We quantify selection factors for V and J gene choice, and for the length and amino-acid composition of the variable region. Our approach is necessary to disentangle the effects of selection from biases inherent in the recombination process. Inferred selection factors differ little between donors, or between naive and memory repertoires. The number of sequences shared between donors is well-predicted by the model, indicating a purely stochastic origin of such "public" sequences. We find a significant correlation between biases induced by VDJ recombination and our inferred selection factors, together with a reduction of diversity during selection. Both effects suggest that natural selection acting on the recombination process has anticipated the selection pressures experienced during somatic evolution.
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