Dominant selection of an invariant T cell antigen receptor in response to persistent infection by Epstein-Barr virus.

Argaet, Victor P.; Schmidt, Chris; Burrows, Scott R.; Silins, Sharon L.; Kurilla, Mike G.; Doolan, Denise L.; Suhrbier, Andreas; Moss, Denis J.; Kieff, E; Sculley, T. B.; Misko, Ihor S.

doi:10.1084/jem.180.6.2335

Cited by 264 publications

(257 citation statements)

References 24 publications

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“…To identify additional sequence constraints that could predict the functional avidity of Ag recognition of A2/melan-A multimer ϩ CD8 ϩ T cells we compared TCR sequences from A2/melan-A multimer ϩ clones described in this study and recently analyzed TCR sequences of melan-A-specific CTL clones from melanoma patients (23). Within defined V␣-J␣ rearrangements, we found some CDR3␣ sequences (Table III) that were either identical (public sequences) or highly homologous among clones derived from different donors, as previously reported for high affinity T cells selected by chronic exposure to Ag (35,36). In contrast, no public or highly homologous sequences were found in the CDR3␤.…”

Section: Resultsmentioning

confidence: 70%

Prevalent Role of TCR α-Chain in the Selection of the Preimmune Repertoire Specific for a Human Tumor-Associated Self-Antigen

Dietrich

Gal

Dutoit

et al. 2003

The Journal of Immunology

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The specificity of recognition of pMHC complexes by T lymphocytes is determined by the V regions of the TCR α- and β-chains. Recent experimental evidence has suggested that Ag-specific TCR repertoires may exhibit a more Vα- than Vβ-restricted usage. Whether Vα usage is narrowed during immune responses to Ag or if, on the contrary, restricted Vα usage is already defined at the early stages of TCR repertoire selection, however, has remained unexplored. Here, we analyzed V and CDR3 TCR regions of single circulating naive T cells specifically detected ex vivo and isolated with HLA-A2/melan-A peptide multimers. Similarly to what was previously observed for melan-A-specific Ag-experienced T cells, we found a relatively wide Vβ usage, but a preferential Vα 2.1 usage. Restricted Vα 2.1 usage was also found among single CD8+ A2/melan-A multimer+ thymocytes, indicating that Vα-restricted selection takes place in the thymus. Vα 2.1 usage, however, was independent from functional avidity of Ag recognition. Thus, interaction of the pMHC complex with selected Vα-chains contributes to set the broad Ag specificity, as underlined by preferential binding of A2/melan-A multimers to Vα 2.1-bearing TCRs, whereas functional outcomes result from the sum of these with other interactions between pMHC complex and TCR.

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Section: Resultsmentioning

confidence: 70%

Prevalent Role of TCR α-Chain in the Selection of the Preimmune Repertoire Specific for a Human Tumor-Associated Self-Antigen

Dietrich

Gal

Dutoit

et al. 2003

The Journal of Immunology

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“…3B). It is notable that both the public TCR b-chain and the a-chain used by these clones each includes just three amino acids that are not germline encoded, which helps to explain the recurrence of this common b-chain in unrelated individuals (3,8). For the public TCR b-chain, these were the central proline-X-arginine CDR3 residues where the X position was one of seven different amino acids observed across all the donors (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The residual repertoire of unique TCRs following thymic selection is between 10 and 100 million in humans (1). Despite this vast potential repertoire, immune responses often show strong bias in TCR selection, resulting in immunodominance of certain "public" TCRs that are widely used in individuals with shared MHC types (2)(3)(4)(5). Structural studies have shown that biased TCR usage arises from unique specificity requirements for a given peptide-MHC complex (6,7).…”

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confidence: 99%

The Impact of a Large and Frequent Deletion in the Human TCR β Locus on Antiviral Immunity

Brennan

Petersen

Neller

et al. 2012

The Journal of Immunology

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The TCR plays a critical role in recognizing intracellular pathogens and initiating pathways leading to the destruction of infected cells by the immune system. Although genetic variability is known to greatly impact on the human immune system and the outcome of infection, the influence of sequence variation leading to the inactivation or deletion of TCR gene segments is unknown. To investigate this issue, we examined the CD8+ T cell response to an HLA-B7–restricted epitope (265RPHERNGFTVL275) from the pp65 Ag of human CMV that was highly biased and frequently dominated by a public TCR β-chain encoded by the variable gene segment TRBV4-3. Approximately 40% of humans lack T cells expressing TRBV4-3 because of a 21.5-kb insertion/deletion polymorphism, but these individuals remain responsive to this epitope, using a diverse T cell repertoire characterized by private TCR usage. Although most residues within the bulged 11-mer peptide were accessible for TCR contact, the public and private TCRs showed distinct patterns of sensitivity to amino acid substitution at different positions within the peptide, thereby suggesting that the repertoire diversity generated in the absence of the dominant public TRBV4-3+ TCR could lead to better protection from viral escape mutation. Thus, variation in the size of the TRBV repertoire clearly contributes toward interindividual variability in immune responses and is presumably maintained in many ethnic groups to enhance the diversity of Ag-specific T cell responses.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Elhanati

Sethna

Callan

et al. 2018

Immunological Reviews

125

159

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SummaryDespite the extreme diversity of T‐cell repertoires, many identical T‐cell receptor (TCR) sequences are found in a large number of individual mice and humans. These widely shared sequences, often referred to as “public,” have been suggested to be over‐represented due to their potential immune functionality or their ease of generation by V(D)J recombination. Here, we show that even for large cohorts, the observed degree of sharing of TCR sequences between individuals is well predicted by a model accounting for the known quantitative statistical biases in the generation process, together with a simple model of thymic selection. Whether a sequence is shared by many individuals is predicted to depend on the number of queried individuals and the sampling depth, as well as on the sequence itself, in agreement with the data. We introduce the degree of publicness conditional on the queried cohort size and the size of the sampled repertoires. Based on these observations, we propose a public/private sequence classifier, “PUBLIC” (Public Universal Binary Likelihood Inference Classifier), based on the generation probability, which performs very well even for small cohort sizes.

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Dominant selection of an invariant T cell antigen receptor in response to persistent infection by Epstein-Barr virus.

Cited by 264 publications

References 24 publications

Prevalent Role of TCR α-Chain in the Selection of the Preimmune Repertoire Specific for a Human Tumor-Associated Self-Antigen

Prevalent Role of TCR α-Chain in the Selection of the Preimmune Repertoire Specific for a Human Tumor-Associated Self-Antigen

The Impact of a Large and Frequent Deletion in the Human TCR β Locus on Antiviral Immunity

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

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