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Estimating the diversity, completeness, and cross-reactivity of the T cell repertoire - PubMed

  • ️Tue Jan 01 2013

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Estimating the diversity, completeness, and cross-reactivity of the T cell repertoire

Veronika I Zarnitsyna et al. Front Immunol. 2013.

Abstract

In order to recognize and combat a diverse array of pathogens the immune system has a large repertoire of T cells having unique T cell receptors (TCRs) with only a few clones specific for any given antigen. We discuss how the number of different possible TCRs encoded in the genome (the potential repertoire) and the number of different TCRs present in an individual (the realized repertoire) can be measured. One puzzle is that the potential repertoire greatly exceeds the realized diversity of naïve T cells within any individual. We show that the existing hypotheses fail to explain why the immune system has the potential to generate far more diversity than is used in an individual, and propose an alternative hypothesis of "evolutionary sloppiness." Another immunological puzzle is why mice and humans have similar repertoires even though humans have over 1000-fold more T cells. We discuss how the idea of the "protecton," the smallest unit of protection, might explain this discrepancy and estimate the size of "protecton" based on available precursor frequencies data. We then consider T cell cross-reactivity - the ability of a T cell clone to respond to more than one epitope. We extend existing calculations to estimate the extent of expected cross-reactivity between the responses to different pathogens. Our results are consistent with two observations: a low probability of observing cross-reactivity between the immune responses to two randomly chosen pathogens; and the ensemble of memory cells being sufficiently diverse to generate cross-reactive responses to new pathogens.

Keywords: cross-reactivity; pathogen recognition; precursor frequency; repertoire; αβ T cell.

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Figures

Figure 1
Figure 1

Plot of the frequency distribution in the β chain sequences of naïve CD8 T cells. Naïve (CD44lo) CD8 T cells from C57Bl/6 mice were isolated by magnetic beads and >98% purity confirmed by flow cytometry. Genomic DNA was subjected to TCRβ V-J multiplex DNA sequencing and the distribution of unique in-frame CDR3 sequences is plotted. We note that the term “clone” on the x and y axis labels refers to clones based on β chain sequences alone.

Figure 2
Figure 2

The probability a pathogen is not detected, PE, as a function of the log of the precursor frequency p and the log of the naïve T cell repertoire R. The numbers on the contour lines in the plot indicate log PE values. Black color corresponds to the values of PE below the threshold of 10−10.

Figure 3
Figure 3

Density distribution plotted from the precursor frequencies of naïve CD8 T cells for different epitopes reported in (31). The tick marks on the top of the x-axis indicate individual epitopes. Note the log scale on the x-axis.

Figure 4
Figure 4

Probability that a pathogen is not recognized PE (y-axis) is plotted as a function of the repertoire (x-axis) for indicated pathogen-specific precursor frequencies (gray lines). LCMV case (p = 4 × 10−5) is shown in red color.

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