Genetic and structural basis for selection of a ubiquitous T cell receptor deployed in Epstein-Barr virus infection

Miles, John J., Bulek, Anna M., Cole, David k., Gostick, Emma, Schauenburg, Andrea J.A., Dolton, Garry, Venturi, Vanessa, Davenport, Miles P., Tan, Mai Ping, Burrows, Scott, Wooldridge, Linda, Price, David A., Rizkallah, Pierre J., and Sewell, Andrew K. (2010) Genetic and structural basis for selection of a ubiquitous T cell receptor deployed in Epstein-Barr virus infection. PLoS Pathogens, 6 (11). pp. 1-15.

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Abstract

Despite the ∼10¹⁸ αβ T cell receptor (TCR) structures that can be randomly manufactured by the human thymus, some surface more frequently than others. The pinnacles of this distortion are public TCRs, which exhibit amino acid-identical structures across different individuals. Public TCRs are thought to result from both recombinatorial bias and antigen-driven selection, but the mechanisms that underlie inter-individual TCR sharing are still largely theoretical. To examine this phenomenon at the atomic level, we solved the co-complex structure of one of the most widespread and numerically frequent public TCRs in the human population. The archetypal AS01 public TCR recognizes an immunodominant BMLF1 peptide, derived from the ubiquitous Epstein-Barr virus, bound to HLA-A*0201. The AS01 TCR was observed to dock in a diagonal fashion, grasping the solvent exposed peptide crest with two sets of complementarity-determining region (CDR) loops, and was fastened to the peptide and HLA-A*0201 platform with residue sets found only within TCR genes biased in the public response. Computer simulations of a random V(D)J recombination process demonstrated that both TCRα and TCRβ amino acid sequences could be manufactured easily, thereby explaining the prevalence of this receptor across different individuals. Interestingly, the AS01 TCR was encoded largely by germline DNA, indicating that the TCR loci already comprise gene segments that specifically recognize this ancient pathogen. Such pattern recognition receptor-like traits within the αβ TCR system further blur the boundaries between the adaptive and innate immune systems.

Item ID: 45234
Item Type: Article (Refereed Research - C1)
Additional Information:

© 2010 Miles et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ISSN: 1553-7374
Funders: National Health and Medical Research Council (NHMRC), Wales Office of Research and Development (WORD), Leverhulme Trust (LT), Australian Research Council (ARC), Wellcome Trust (WT), Medical Research Council (MRC), Research Councils UK (RCUK), Biotechnology and Biological Sciences Research Council (BBSRC)
Projects and Grants: BBSRC Grant BB/H001085/1
Date Deposited: 05 Sep 2016 02:26
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110702 Applied Immunology (incl Antibody Engineering, Xenotransplantation and T-cell Therapies) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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