TCRα Genes Direct MHC Restriction in the Potent Human T Cell Response to a Class I-Bound Viral Epitope
| Autor: | John J. Miles, Fleur Elizabeth Tynan, Scott R. Burrows, Lars Kjer-Nielsen, Natalie A. Borg, Jacqueline M. Burrows, James McCluskey, Rebekah M Brennan, Sharon L. Silins, Melissa J. Bell, Jamie Rossjohn |
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| Rok vydání: | 2006 |
| Předmět: |
Cytotoxicity
Immunologic Receptors Antigen T-Cell alpha-beta T cell Molecular Sequence Data Immunology Epitopes T-Lymphocyte chemical and pharmacologic phenomena Human leukocyte antigen Biology Crystallography X-Ray Epitope Antigen HLA Antigens medicine Humans Immunology and Allergy Cytotoxic T cell Amino Acid Sequence Cells Cultured Cell Line Transformed Genetics Antigen Presentation Histocompatibility Antigens Class I T-cell receptor MHC restriction Cell biology Protein Subunits CTL medicine.anatomical_structure Epstein-Barr Virus Nuclear Antigens HLA-B Antigens HLA-B35 Antigen Protein Binding T-Lymphocytes Cytotoxic |
| Zdroj: | The Journal of Immunology. 177:6804-6814 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.177.10.6804 |
| Popis: | The underlying generic properties of αβ TCRs that control MHC restriction remain largely unresolved. To investigate MHC restriction, we have examined the CTL response to a viral epitope that binds promiscuously to two human leukocyte Ags (HLAs) that differ by a single amino acid at position 156. Individuals expressing either HLA-B*3501 (156Leucine) or HLA-B*3508 (156Arginine) showed a potent CTL response to the 407HPVGEADYFEY417 epitope from EBV. Interestingly, the response was characterized by highly restricted TCR β-chain usage in both HLA-B*3501+ and HLA-B*3508+ individuals; however, this conserved TRBV9+ β-chain was associated with distinct TCR α-chains depending upon the HLA-B*35 allele expressed by the virus-exposed host. Functional assays confirmed that TCR α-chain usage determined the HLA restriction of the CTLs. Structural studies revealed significant differences in the mobility of the peptide when bound to HLA-B*3501 or HLA-B*3508. In HLA-B*3501, the bulged section of the peptide was disordered, whereas in HLA-B*3508 the bulged epitope adopted an ordered conformation. Collectively, these data demonstrate not only that mobile MHC-bound peptides can be highly immunogenic but can also stimulate an extremely biased TCR repertoire. In addition, TCR α-chain usage is shown to play a critical role in controlling MHC restriction between closely related allomorphs. |
| Databáze: | OpenAIRE |
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