Genetic and Structural Basis for Selection of a Ubiquitous T Cell Receptor Deployed in Epstein-Barr Virus Infection

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. The human immune recombination machinery can generate approximately 10¹⁸ unique αβ T cell receptor structures. The recombination event, once thought to be random, has now been shown to involve enzymatic biases during chromosomal rearrangement; additional biases occur during thymic selection and antigen-driven expansion in the periphery. 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. One of the most prominent public T cell responses found in humans is raised against the GLCTLVAML (GLC) peptide from Epstein-Barr virus. We, and 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. Here, we investigate the genetic, biophysical and structural forces that drive this public receptor, designated AS01, with in silico estimates of relative production frequencies during gene recombination, thermodynamic scanning and crystallographic studies of the AS01-GLC-A2 complex. We find that the TCRα and TCRβ amino acid sequences of AS01 are produced efficiently by a process of convergent recombination and employ unique residues, encoded only by the above-mentioned genes, to engage antigen in a highly specific manner.