The Impact of a Large and Frequent Deletion in the Human TCR β Locus on Antiviral Immunity
Open Access
- 15 March 2012
- journal article
- Published by The American Association of Immunologists
- Vol. 188 (6), 2742-2748
- https://doi.org/10.4049/jimmunol.1102675
Abstract
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.Keywords
This publication has 29 references indexed in Scilit:
- Bias in the αβ T‐cell repertoire: implications for disease pathogenesis and vaccinationImmunology & Cell Biology, 2011
- Constraints within major histocompatibility complex class I restricted peptides: Presentation and consequences for T-cell recognitionProceedings of the National Academy of Sciences of the United States of America, 2010
- PHENIX: a comprehensive Python-based system for macromolecular structure solutionActa Crystallographica Section D-Structural Biology, 2010
- T-cell receptor bias and immunityCurrent Opinion in Immunology, 2008
- T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I–bound peptideNature Immunology, 2005
- Coot: model-building tools for molecular graphicsActa Crystallographica Section D-Biological Crystallography, 2004
- Sequence Variation and Linkage Disequilibrium in the Human T-Cell Receptor β (TCRB) LocusAmerican Journal of Human Genetics, 2001
- Refinement of Macromolecular Structures by the Maximum-Likelihood MethodActa Crystallographica Section D-Biological Crystallography, 1997
- Human leukocyte antigen phenotype imposes complex constraints on the antigen‐specific cytotoxic T lymphocyte repertoireEuropean Journal of Immunology, 1997
- T-Cell receptor BV6S1 null alleles and HLA-DR1 haplotypes in polyarticular outcome juvenile rheumatoid arthritisHuman Immunology, 1996