The Role of Production Frequency in the Sharing of Simian Immunodeficiency Virus-Specific CD8+ TCRs between Macaques

Abstract

In some epitope-specific responses, T cells bearing identical TCRs occur in many MHC-matched individuals. The sharing of public TCRs is unexpected, given the enormous potential diversity of the TCR repertoire. We have previously studied the sharing of TCR β-chains in the CD8+ T cell responses to two influenza epitopes in mice. Analysis of these TCRβ repertoires suggests that, even with unbiased V(D)J recombination mechanisms, some TCRβs can be produced more frequently than others, by a process of convergent recombination. The TCRβ production frequency was shown to be a good predictor of the observed sharing of epitope-specific TCRβs between mice. However, this study was limited to immune responses in an inbred population. In this study, we investigated TCRβ sharing in CD8+ T cell responses specific for the immunodominant Mamu-A*01-restricted Tat-SL8/TL8 and Gag-CM9 epitopes of SIV in rhesus macaques. Multiple data sets were used, comprising a total of ∼6000 TCRβs sampled from 20 macaques. We observed a spectrum in the number of macaques sharing epitope-specific TCRβs in this outbred population. This spectrum of TCRβ sharing was negatively correlated with the minimum number of nucleotide additions required to produce the sequences and strongly positively correlated with the number of observed nucleotide sequences encoding the amino acid sequences. We also found that TCRβ sharing was correlated with the number of times, and the variety of different ways, the sequences were produced in silico via random gene recombination. Thus, convergent recombination is a major determinant of the extent of TCRβ sharing.

Determinants of public T cell responses

“…Through computer simulation, the authors estimated the relative production frequencies and varieties of production mechanisms for TCR β sequences and found strong correlations with the sharing of both TCR β amino-acid sequences and TCR β nucleotide sequences [38]. The same group further confirmed the role of convergent recombination in driving the sharing of TCR sequences in outbred macaques [39] and humans [40]. By analyzing 6 000 TCR β  sequences that are specific for the immunodominant Mamu-A*01-restricted Tat-SL8/TL8 and Gag-CM9 epitopes of SIV in 20 outbred rhesus macaques, they observed that the spectrum of TCR β sharing was negatively correlated with the minimum number of nucleotide additions required to produce the sequences and strongly positively correlated with the number of observed nucleotide sequences encoding the amino-acid sequences.…”

“…The available data suggest that convergent recombination [37][38][39][40] and biases during recombination [33,37,41] are the major contributors of TCR sharing in TCR repertoires among individuals. Convergent recombination is the process whereby multiple recombination events 'converge' to produce the same nucleotide sequence and multiple nucleotide sequences "converge" to encode the same amino-acid sequence (Figure 1), which results in different TCR sequences to be generated with differential frequencies during recombination [37][38][39][40].…”

“…Convergent recombination is the process whereby multiple recombination events 'converge' to produce the same nucleotide sequence and multiple nucleotide sequences "converge" to encode the same amino-acid sequence (Figure 1), which results in different TCR sequences to be generated with differential frequencies during recombination [37][38][39][40]. Recombinatorial biases include biased V/D/J gene usage and combination, bias in the number of nucleotide deletions at the coding ends of V/D/J gene segments, bias in the number of nucleotide additions and bias in base usage at the V-D/ D-J junctions [33,37,[41][42][43].…”

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

“…The resulting “repertoire” of distinct TCRs expressed in an individual defines a unique footprint of immune protection. Despite this diversity, a significant overlap in the TCR response of different individuals to a variety of antigens and infections has been observed in humans,2, 3, 4 mice,5, 6, 7 and macaques8 (reviewed in 9, 10). This observation led to the notion of a “public” response shared by all, and a complementary “private” response specific to each individual 5.…”

“…Since antigen‐specific TCRs have a restricted set of sequences,11, 12 and since there is no identified analog for T cells of B‐cell affinity maturation, a public response can only arise if the specific responding T cells are independently generated in each individual's T‐cell repertoire. 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.…”