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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    • "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.
    Proceedings of the National Academy of Sciences 04/2014; 111(27). DOI:10.1073/pnas.1409572111 · 9.81 Impact Factor
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    • "Given the relatively small number of CD4 + naïve T cells used, we expected that the actual TCR β chain diversity in each sample should be equal to the number of cells in that sample (Fig. 5). This expectation may not have been fully correct: multiple cells in the samples may have shared identical TCRβ rearrangements due to homeostatic proliferation , phenotype reversion of atypical memory cells, and the fact that some TCR rearrangements are far more likely to occur than others (Quigley et al., 2010). In fact, the measured values were generally within a factor of two of the expected value. "
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