TCR β-Chain Sharing in Human CD8+ T Cell Responses to Cytomegalovirus and EBV

Abstract

The CD8؉ TCR repertoires specific for many immunogenic epitopes of CMV and EBV are dominated by a few TCR clonotypes and involve public TCRs that are shared between many MHC-matched individuals. In previous studies, we demonstrated that the observed sharing of epitope-specific TCR␤ chains between individuals is strongly associated with TCR␤ production frequency, and that a process of convergent recombination facilitates the more efficient production of some TCR␤ sequences. In this study, we analyzed a total of 2836 TCR␤ sequences from 23 CMV-infected and 10 EBV-infected individuals to investigate the factors that influence the sharing of TCR␤ sequences in the CD8 ؉ T cell responses to two immunodominant HLA-A*0201-restricted epitopes from these viruses. The most shared TCR␤ amino acid sequences were found to have two features that indicate efficient TCR␤ production, as follows: 1) they required fewer nucleotide additions, and 2) they were encoded by a greater variety of nucleotide sequences. We used simulations of random V(D)J recombination to demonstrate that the in silico TCR␤ production frequency was predictive of the extent to which both TCR␤ nucleotide and amino acid sequences were shared in vivo. These results suggest that TCR␤ production frequency plays an important role in the interindividual sharing of TCR␤ sequences within CD8 ؉ T cell responses specific for CMV and EBV.

Large TCR Diversity of Virus-Specific CD8 T Cells Provides the Mechanistic Basis for Massive TCR Renewal after Antigen Exposure

“…The conservation of this N-encoded sequence suggested Ag-driven selection of this clonotype. Of note, two clonotypes found in response to CMV NLVPMVATV were also found by anchored RT-PCR and sequencing of subclones in previous studies (19,20). With regard to EBV-specific CD8 T cells, the same degree of clonotypic diversity was found for two epitopes (Fig.…”

“…In addition, it has been shown that the TCR repertoire directed against a particular CMV-derived epitope remained quite heterogeneous in healthy individuals (15). Along the same line, direct sequencing of the TCR b-chain by anchored PCR on ex vivo virus-specific sorted CD8 T cells revealed that two epitopes derived from EBV and CMV were recognized by CD8 T cells exhibiting a higher degree (seven to nine clonotypes) of clonotypic diversity (19,20) indicating that the TCR repertoire during viral response might not be as restricted as thought. The variable degree of diversity of the TCR repertoire observed during chronic virus infections might be related to the experimental strategies used in various studies.…”

“…Conserved CDR3 residues found in the current study are highlighted in yellow. Public clonotypes found in previous studies (19,20) are shown in blue boxes.…”

“…Many studies have analyzed the TCR repertoire in T cell lines and/or clones obtained in vitro from a limited number of subjects (21,22) and/or have been based on the use of an incomplete panel of anti-Vb mAbs (14,15,(21)(22)(23), raising the question of to what extent these data were representative of the in vivo situation. With regard to the direct sequencing of the TCR b-chain by anchored PCR in ex vivo Ag-specific sorted cells (19,20,24), it is possible that the TCR repertoire diversity might be underestimated, as the degree of diversity measured will be dependent upon the extent of sequencing with the potential for preferential detection of dominant CD8 T cell clonotypes.…”

Half of the T‐cell repertoire combinatorial diversity is genetically determined in humans and humanized mice

“…Furthermore, the high representation of some V-J combinations in humans and in humanized mice suggests a similar mechanism of selection, independently of the donor genotype and/or of the immunological history of the subject. In that regard, it is striking to note that, in the few studies that describe public TCR (T-cell clones conserved in various human afflictions among different patients), most belong to highly conserved hTRBV families that we describe here (the BV19 gene for Influenza infection [24], the BV6 family for HCMV [25] and SIV [26] infections, and the BV20 gene for EBV infection [27,28]. This correlation is not restricted to viral infections since the BV4 and BV12 families are also commonly used in autoimmune anti-phospholipid syndrome [29]).…”