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

Journal Article · · mBio (Online)
 [1];  [2];  [3];  [4];  [4];  [3];  [2];  [4]
  1. Univ. of Massachusetts, Worcester, MA (United States). Dept. of Pathology; DOE/OSTI
  2. Univ. of Massachusetts, Worcester, MA (United States). program in Molecular Medicine
  3. Univ. of Nebraska Medical Center, Omaha, NE (United States). School of Interdisciplinary Informatics
  4. Univ. of Massachusetts, Worcester, MA (United States). Dept. of Pathology
+ Show Author Affiliations

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, TCRα CDR3 motifs played a dominant role, while TCRβ 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 TCRβ CDR3 interactions with peptide/major histocompatibility complex (MHC) or in combination with TCRα 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1629656
Journal Information:
mBio (Online), Journal Name: mBio (Online) Journal Issue: 2 Vol. 11; ISSN 2150-7511
Publisher:
American Society for Microbiology (ASM)Copyright Statement
Country of Publication:
United States
Language:
English

References (73)

Disease etiology and diagnosis by TCR repertoire analysis goes viral journal November 2016
T cell receptor alpha variable 12-2 bias in the immunodominant response to Yellow fever virus journal December 2017
The human t cell antigen receptor is encoded by variable, diversity, and joining gene segments that rearrange to generate a complete V gene journal June 1984
Sequence and Structural Analyses Reveal Distinct and Highly Diverse Human CD8 + TCR Repertoires to Immunodominant Viral Antigens journal April 2017
The Structural Dynamics and Energetics of an Immunodominant T Cell Receptor Are Programmed by Its Vβ Domain journal February 2008
A small jab – a big effect: nonspecific immunomodulation by vaccines journal September 2013
Unique influenza A cross-reactive memory CD8 T-cell receptor repertoire has a potential to protect against EBV seroconversion journal October 2017
The need and challenges for development of an Epstein-Barr virus vaccine journal April 2013
Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system journal April 1974
A human T cell-specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains journal March 1984
Isolation of cDNA clones encoding T cell-specific membrane-associated proteins journal March 1984
αβ T cell receptors as predictors of health and disease journal January 2015
Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapy journal October 2014
Defective T-cell control of Epstein–Barr virus infection in multiple sclerosis journal January 2017
Bias in the αβ T‐cell repertoire: implications for disease pathogenesis and vaccination journal February 2011
Maintenance of the EBV‐specific CD8 + TCRαβ repertoire in immunosuppressed lung transplant recipients journal October 2016
Quantifiable predictive features define epitope-specific T cell receptor repertoires journal June 2017
Identifying specificity groups in the T cell receptor repertoire journal June 2017
Linking T-cell receptor sequence to functional phenotype at the single-cell level journal June 2014
Immunosequencing identifies signatures of cytomegalovirus exposure history and HLA-mediated effects on the T cell repertoire journal April 2017
T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I–bound peptide journal September 2005
T-cell therapy in the treatment of post-transplant lymphoproliferative disease journal July 2012
The many important facets of T-cell repertoire diversity journal February 2004
The molecular basis for public T-cell responses? journal March 2008
No one is naive: the significance of heterologous T-cell immunity journal June 2002
MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape journal February 2017
Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8+ T cell epitope journal February 2017
Understanding the drivers of MHC restriction of T cell receptors journal April 2018
Post-transplant lymphoproliferative disorder: a review journal February 2003
Infectious Mononucleosis journal May 2010
Insulin Needs after CD3-Antibody Therapy in New-Onset Type 1 Diabetes journal June 2005
Sharing of T cell receptors in antigen-specific responses is driven by convergent recombination journal November 2006
Reproducible selection of high avidity CD8+ T-cell clones following secondary acute virus infection journal January 2014
Structural Basis for Clonal Diversity of the Public T Cell Response to a Dominant Human Cytomegalovirus Epitope journal October 2015
Structural basis for clonal diversity of the human T-cell response to a dominant influenza virus epitope journal November 2017
High Resolution Structures of Highly Bulged Viral Epitopes Bound to Major Histocompatibility Complex Class I: IMPLICATIONS FOR T-CELL RECEPTOR ENGAGEMENT AND T-CELL IMMUNODOMINANCE journal April 2005
Dominant selection of an invariant T cell antigen receptor in response to persistent infection by Epstein-Barr virus. journal December 1994
OLGA: fast computation of generation probabilities of B- and T-cell receptor amino acid sequences and motifs journal January 2019
Biology and disease associations of Epstein–Barr virus journal April 2001
Circos: An information aesthetic for comparative genomics journal June 2009
Memory of mice and men: CD8+ T-cell cross-reactivity and heterologous immunity journal June 2006
T-Cell Receptor V-Region Usage and Antigen Specificity.: The Cytochrome c Model System journal July 1995
Cytomegalovirus infection enhances the immune response to influenza journal April 2015
Narrowing of Human Influenza A Virus-Specific T Cell Receptor α and β Repertoires with Increasing Age journal January 2015
Early Therapy of Vertical Human Immunodeficiency Virus Type 1 (HIV-1) Infection: Control of Viral Replication and Absence of Persistent HIV-1-Specific Immune Responses journal August 2000
Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires journal December 2017
The Immunology of Epstein-Barr Virus–Induced Disease journal March 2015
CD8+ T-cell selection, function, and death in the primary immune response in vivo journal November 2000
Cross-reactive influenza virus-specific CD8+ T cells contribute to lymphoproliferation in Epstein-Barr virus-associated infectious mononucleosis journal December 2005
Sustained Complete Responses in Patients With Lymphoma Receiving Autologous Cytotoxic T Lymphocytes Targeting Epstein-Barr Virus Latent Membrane Proteins journal March 2014
Genetic and Structural Basis for Selection of a Ubiquitous T Cell Receptor Deployed in Epstein-Barr Virus Infection journal November 2010
Deep Sequencing of Antiviral T-Cell Responses to HCMV and EBV in Humans Reveals a Stable Repertoire That Is Maintained for Many Years journal September 2012
Selective expansion of high functional avidity memory CD8 T cell clonotypes during hepatitis C virus reinfection and clearance journal February 2017
CDR3α drives selection of the immunodominant Epstein Barr virus (EBV) BRLF1-specific CD8 T cell receptor repertoire in primary infection journal November 2019
Frontiers in Nephrology: Heterologous Immunity, T Cell Cross-Reactivity, and Alloreactivity journal July 2007
Heterologous immunity: Immunopathology, autoimmunity and protection during viral infections journal January 2011
Interpreting T-Cell Cross-reactivity through Structure: Implications for TCR-Based Cancer Immunotherapy journal October 2017
Single-Cell Approach to Influenza-Specific CD8+ T Cell Receptor Repertoires Across Different Age Groups, Tissues, and Following Influenza Virus Infection journal June 2018
CD8 T Cell Cross-Reactivity Networks Mediate Heterologous Immunity in Human EBV and Murine Vaccinia Virus Infections journal February 2010
Broad Cross-Reactive TCR Repertoires Recognizing Dissimilar Epstein-Barr and Influenza A Virus Epitopes journal November 2010
Naive T Cell Repertoire Skewing in HLA-A2 Individuals by a Specialized Rearrangement Mechanism Results in Public Memory Clonotypes journal January 2011
A Mechanism for TCR Sharing between T Cell Subsets and Individuals Revealed by Pyrosequencing journal March 2011
CD8 + TCR Bias and Immunodominance in HIV-1 Infection journal April 2015
Frequent Contribution of T Cell Clonotypes with Public TCR Features to the Chronic Response Against a Dominant EBV-Derived Epitope: Application to Direct Detection of Their Molecular Imprint on the Human Peripheral T Cell Repertoire journal August 2000
Changing Patterns of Dominant TCR Usage with Maturation of an EBV-Specific Cytotoxic T Cell Response journal November 2000
Differential Kinetics and Specificity of EBV-Specific CD4 + and CD8 + T Cells During Primary Infection journal March 2003
Emerging Concepts in TCR Specificity: Rationalizing and (Maybe) Predicting Outcomes journal September 2017
Vα and Vβ Public Repertoires Are Highly Conserved in Terminal Deoxynucleotidyl Transferase-Deficient Mice journal December 2004
Multiple Glycines in TCR α-Chains Determine Clonally Diverse Nature of Human T Cell Memory to Influenza A Virus journal November 2008
TCR β-Chain Sharing in Human CD8 + T Cell Responses to Cytomegalovirus and EBV journal November 2008
The Role of Production Frequency in the Sharing of Simian Immunodeficiency Virus-Specific CD8 + TCRs between Macaques journal August 2008
Hepatitis C Virus Immune Escape via Exploitation of a Hole in the T Cell Repertoire journal October 2008
Human T cell receptor occurrence patterns encode immune history, genetic background, and receptor specificity journal August 2018

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
EBV
Epstein-Barr virus
T cell receptor
TCR
acute infectious mononucleosis
repertoire