Epstein-Barr Virus Epitope-Major Histocompatibility Complex Interaction Combined with Convergent Recombination Drives Selection of Diverse T Cell Receptor alpha and beta Repertoires

Recognition modes of individual T cell receptors (TCRs) are well studied, but factors driving the selection of TCR repertoires from primary through persistent human virus infections are less well understood. Using deep sequencing, we demonstrate a high degree of diversity of Epstein-Barr virus (EBV)-specific clonotypes in acute infectious mononucleosis (AIM). Only 9% of unique clonotypes detected in AIM persisted into convalescence; the majority (91%) of unique clonotypes detected in AIM were not detected in convalescence and were seeming replaced by equally diverse “de novo” clonotypes. The persistent clonotypes had a greater probability of being generated than nonpersistent clonotypes due to convergence recombination of multiple nucleotide sequences to encode the same amino acid sequence, as well as the use of shorter complementarity-determining regions 3 (CDR3s) with fewer nucleotide additions (i.e., sequences closer to germ line). Moreover, the two most immunodominant HLA-A2-restricted EBV epitopes, BRLF1109 and BMLF1280, show highly distinct antigen-specific public (i.e., shared between individuals) features. In fact, TCR CDR3 motifs played a dominant role, while TCR played a minimal role, in the selection of TCR repertoire to an immunodominant EBV epitope, BRLF1. This contrasts with the majority of previously reported repertoires, which appear to be selected either on TCR CDR3 interactions with peptide/major histocompatibility complex (MHC) or in combination with TCR CDR3. Understanding of how TCR-peptide-MHC complex interactions drive repertoire selection can be used to develop optimal strategies for vaccine design or generation of appropriate adoptive immunotherapies for viral infections in transplant settings or for cancer. IMPORTANCE Several lines of evidence suggest that TCR and TCR repertoires play a role in disease outcomes and treatment strategies during viral infections in transplant patients and in cancer and autoimmune disease therapy. Our data suggest that it is essential that we understand the basic principles of how to drive optimum repertoires for both TCR chains, and . We address this important issue by characterizing the CD8 TCR repertoire to a common persistent human viral infection (EBV), which is controlled by appropriate CD8 T cell responses. The ultimate goal would be to determine if the individuals who are infected asymptomatically develop a different TCR repertoire than those that develop the immunopathology of AIM. Here, we begin by doing an in-depth characterization of both CD8 T cell TCR and TCR repertoires to two immunodominant EBV epitopes over the course of AIM, identifying potential factors that may be driving their selection. Citation Gil A, Kamga L, Chirravuri-Venkata R, Aslan N, Clark F, Ghersi D, Luzuriaga K, Selin LK. 2020. Epstein-Barr virus epitope–major histocompatibility complex interaction combined with convergent recombination drives selection of diverse T cell receptor α and β repertoires. mBio 11:e00250-20. https://doi . org/10.1128/mBio.00250-20. Editor Jack R. Bennink, National Institute of Allergy and Infectious Diseases Copyright © 2020 Gil et al. This is an openaccess article distributed under the terms of the Creative Commons Attribution 4.0 International license. Address correspondence to Katherine Luzuriaga, katherine.luzuriaga@umassmed.edu, or Liisa K. Selin, liisa.selin@umassmed.edu. This article is a direct contribution from Katherine Luzuriaga, a Fellow of the American Academy of Microbiology, who arranged for and secured reviews by Paul Thomas, St. Jude Children's Research Hospital, and Immo Prinz, Hannover Medical School. Received 5 February 2020 Accepted 11 February 2020 Published RESEARCH ARTICLE Host-Microbe Biology