Sharing of T cell receptors in antigen-specific responses is driven by convergent recombination

Abstract

Public responses where identical T cell receptors (TCRs) are clonally dominant and shared between different individuals are a common characteristic of CD8(+) T cell-mediated immunity. Focusing on TCR sharing, we analyzed approximately 3,400 TCR beta chains (TCRbetas) from mouse CD8(+) T cells responding to the influenza A virus D(b)NP(366) and D(b)PA(224) epitopes. Both the "public" D(b)NP(366)-specific and "private" D(b)PA(224)-specific TCR repertoires contain a high proportion ( approximately 36%) of shared TCRbetas, although the numbers of mice sharing TCRbetas in each repertoire varies greatly. Sharing of both the TCRbeta amino acid and TCRbeta nucleotide sequence was negatively correlated with the prevalence of random nucleotide additions in the sequence. However, the extent of TCRbeta amino acid sequence sharing among mice was strongly correlated with the level of diversity in the encoding nucleotide sequences, suggesting that a key feature of public TCRs is that they can be made in a variety of ways. Using a computer simulation of random V(D)J recombination, we estimated the relative production frequencies and variety of production mechanisms for TCRbeta sequences and found strong correlations with the sharing of both TCRbeta amino acid sequences and TCRbeta nucleotide sequences. The overall conclusion is that "convergent recombination," rather than a bias in recombination or subsequent selection, provides the mechanistic basis for TCR sharing between individuals responding to identical peptide plus MHC class I glycoprotein complexes.

Fig. 1.

Sequence analysis of the D^bNP₃₆₆- and D^bPA₂₂₄-specific TCRβ repertoires. The relationship between the number of nucleotide additions in D^bNP₃₆₆- (A) and D^bPA₂₂₄-specific (B) TCRβ sequences and the number of mice in which an amino acid (a.a.) sequence was present. The relationship between the number of different nucleotide (n.t.) sequences encoding an amino acid sequence and the number of mice in which an amino acid sequence was found for the D^bNP₃₆₆- (C) and D^bPA₂₂₄-specific (D) responses. The box-and-whisker plots show the distributions of the number of nucleotide additions or the number of unique nucleotide sequences (vertical axis) for amino acid sequences present in a particular number of mice (horizontal axis). The median and mean are represented as a horizontal bar and an asterisk, respectively. The box represents the 25th and 75th centiles, and the lines represent the maximum and minimum values. The correlation and significance values are based on the Spearman test.

Fig. 2.

Analysis of an in silico TCRβ repertoire with respect to in vivo sharing. The relationship between the number of mice in which a D^bNP₃₆₆-specific (Vβ8.3/Jβ2S2) amino acid (a.a.) sequence was found in vivo and the number of times an amino acid sequence was generated in silico by the simulations (A) and the number of different V(D)J recombination mechanisms producing an amino acid sequence in silico (B). Each point on the graph represents an amino acid sequence that was found in vivo in the experiments, present in a particular number of mice (horizontal axis). On the vertical axis is the number of times (A) or the number of different ways (B) that each amino acid sequence was generated by the simulation. The correlation and significance values are based on the Spearman test.