A Structural Basis for the Selection of Dominant αβ T Cell Receptors in Antiviral Immunity

Kjer‐Nielsen, Lars; Clements, Craig Steven; Purcell, Anthony W.; Brööks, Andrëw G.; Whisstock, James C.; Burrows, Scott R.; McCluskey, James; Rossjohn, Jamie

doi:10.1016/s1074-7613(02)00513-7

Cited by 318 publications

(345 citation statements)

References 53 publications

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“…Previous studies with TCR Tg T cells indicate that such selection reflects differing TCR avidity profiles (37,43). As such, enrichment of TRBV bias from the naive into the immune repertoire is presumably due to the preferential selection/proliferation of CTLps with "optimal-fit" TCRs (37,43,44).…”

Section: Figurementioning

confidence: 99%

Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion

Gruta¹,

Rothwell²,

Cukalac³

et al. 2010

J. Clin. Invest.

145

211

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CD8 + T cell responses to viral infection are characterized by the emergence of dominant and subdominant CTL populations. The immunodominance hierarchies of these populations are highly reproducible for any given spectrum of virus-induced peptide-MHCI complexes and are likely determined by multiple factors. Recent studies demonstrate a direct correlation between naive epitope-specific CD8 + T cell precursor (CTLp) frequency and the magnitude of the response after antigen challenge. Thus, the number of available precursors in the naive pool has emerged as a key predictor of immunodominance. In contrast to this, we report here no consistent relationship between CTLp frequency and the subsequent magnitude of the immune response for 4 influenza virus-derived epitopes following intranasal infection of mice with influenza A virus. Rather, the characteristic, antigen-driven T cell immunodominance hierarchy was determined by the extent of recruitment from the available pool of epitope-specific precursors and the duration of their continued expansion over the course of the infection. These findings suggest possibilities for enhancing protective immune memory by maximizing both the size and diversity of typically subdominant T cell responses through rational vaccine design.

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Section: Figurementioning

confidence: 99%

Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion

Gruta¹,

Rothwell²,

Cukalac³

et al. 2010

J. Clin. Invest.

145

211

View full text Add to dashboard Cite

show abstract

“…Structural analysis of TCRs binding related APLs did not reveal any significant differences in the TCR-pMHC interaction to explain agonist vs antagonist activation (3), but a recent study has identified a conformational change in TCR␣ structure during TCR-pMHC binding (4). This remains to be confirmed in other structures.…”

mentioning

confidence: 90%

TCR Binding Kinetics Measured with MHC Class I Tetramers Reveal a Positive Selecting Peptide with Relatively High Affinity for TCR

Holmberg

Mariathasan

Ohteki

et al. 2003

The Journal of Immunology

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The interaction between TCR and peptide-MHC (pMHC) complexes is crucial for the activation of T cells as well as for positive and negative selection in the thymus. The kinetics and affinity of this interaction and the densities of TCR and pMHC complexes on the cell surface are determining factors for different outcomes during thymic selection. In general, it is thought that agonist pMHC, which cause negative selection, have higher affinities and, in particular, slower off-rates than partial or weak agonists and antagonists, which cause positive selection. In this study, we have used pMHC tetramers to investigate the kinetics of TCR-pMHC interaction for agonist, weak agonist, and antagonist ligands of the anti-lymphocytic choriomeningitis virus P14 TCR. Kinetics determined on the cell surface may be biologically more relevant than methods using soluble proteins. We can distinguish between agonists and weak agonists or antagonists based on the half-life and the avidity of tetramer-TCR interaction. Furthermore, we show that a weak agonist self-peptide that positively selects P14 TCR+ thymocytes has a tetramer half-life and avidity only slightly weaker than strong agonists. We show that, in fact, it can act as quite a strong agonist, but that its poor ability to stabilize MHC causes it instead to have a weak agonist phenotype.

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“…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). Furthermore, TCR production frequency during recombination in the thymus also contributes to bias in TCR usage in Ag-specific responses, with public TCRs generally produced with fewer random nucleotide additions in their sequence (8).…”

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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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A Structural Basis for the Selection of Dominant αβ T Cell Receptors in Antiviral Immunity

Cited by 318 publications

References 53 publications

Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion

Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion

TCR Binding Kinetics Measured with MHC Class I Tetramers Reveal a Positive Selecting Peptide with Relatively High Affinity for TCR

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

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