title: Broadly reactive human CD8 T cells that recognize an epitope conserved between VZV, HSV and EBV.
abstract: Human herpesviruses are important causes of potentially severe chronic infections for which T cells are believed to be necessary for control. In order to examine the role of virus-specific CD8 T cells against Varicella Zoster Virus (VZV), we generated a comprehensive panel of potential epitopes predicted in silico and screened for T cell responses in healthy VZV seropositive donors. We identified a dominant HLA-A*0201-restricted epitope in the VZV ribonucleotide reductase subunit 2 and used a tetramer to analyze the phenotype and function of epitope-specific CD8 T cells. Interestingly, CD8 T cells responding to this VZV epitope also recognized homologous epitopes, not only in the other α-herpesviruses, HSV-1 and HSV-2, but also the γ-herpesvirus, EBV. Responses against these epitopes did not depend on previous infection with the originating virus, thus indicating the cross-reactive nature of this T cell population. Between individuals, the cells demonstrated marked phenotypic heterogeneity. This was associated with differences in functional capacity related to increased inhibitory receptor expression (including PD-1) along with decreased expression of co-stimulatory molecules that potentially reflected their stimulation history. Vaccination with the live attenuated Zostavax vaccine did not efficiently stimulate a proliferative response in this epitope-specific population. Thus, we identified a human CD8 T cell epitope that is conserved in four clinically important herpesviruses but that was poorly boosted by the current adult VZV vaccine. We discuss the concept of a "pan-herpesvirus" vaccine that this discovery raises and the hurdles that may need to be overcome in order to achieve this.
authors.affiliation: Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America; Centre for Respiratory Infection, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chiu
authors.affiliation: Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Megan
authors.initials: M
authors.lastname: McCausland
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.affiliation: Cancer and Inflammation Program, Laboratory for Experimental Immunology, SAIC Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America; Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Fuh-Mei
authors.initials: FM
authors.lastname: Duh
authors.affiliation: Hope Clinic of the Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States of America; Division of Infectious Diseases School of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Nadine
authors.initials: N
authors.lastname: Rouphael
authors.affiliation: Division of Infectious Diseases School of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Aneesh
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Hope Clinic of the Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States of America; Division of Infectious Diseases School of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Mulligan
authors.affiliation: Cancer and Inflammation Program, Laboratory for Experimental Immunology, SAIC Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America; Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.affiliation: Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wieland
authors.affiliation: Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Sullivan
authors.affiliation: Departments of Pediatrics, Medicine and Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Adriana
authors.initials: A
authors.lastname: Weinberg
authors.affiliation: Departments of Pediatrics, Medicine and Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Myron J
authors.initials: MJ
authors.lastname: Levin
authors.affiliation: Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Bali
authors.initials: B
authors.lastname: Pulendran
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.affiliation: Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003429:Cross Reactions; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000276:immunology; D053061:Herpes Zoster Vaccine / Q000276:immunology; D014645:Herpesvirus 3, Human / Q000276:immunology*; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D018139:Simplexvirus / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D053061:Herpes Zoster Vaccine; D014765:Viral Vaccines