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.
Highlights
Epstein-Barr virus (EBV), called human herpesvirus 4 (HHV-4), is a genetically stable agent that has slowly co-evolved with our species and its antecedents for millions of years
The furthest extremes of these collective biases result in public T cell receptors (TCRs), defined as residue-identical receptors found across different individuals who share a common major histocompatibility complex (MHC) allele
Others, have previously shown that a public TCR constructed from the TRBV20-1/TRBJ1-2 and TRAV5/TRAJ31 gene segments dominates the GLC-specific repertoire
Summary
Epstein-Barr virus (EBV), called human herpesvirus 4 (HHV-4), is a genetically stable agent that has slowly co-evolved with our species and its antecedents for millions of years. More than 90% of the world’s population is infected with EBV. This mutual coexistence is not without heavy resource cost for the host. Large populations of CD8+ ab T lymphocytes are deployed for the purposes of EBV surveillance and suppression. These populations peak during asymptomatic primary infection [1], acute infectious mononucleosis (AIM) [2] and old age [3]. Up to 11% of the total peripheral CD8+ T cell pool can be specific for GLC-A2 [4]; this response contracts to 0.5–2.2% of the peripheral CD8+ T cell pool during persistent infection [4], but can swell again to 10% in old age [3]. Given the high in vivo frequencies of this response and the ubiquity of both
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