title: Extensive CD4 and CD8 T Cell Cross-Reactivity between Alphaherpesviruses.
abstract: The Alphaherpesvirinae subfamily includes HSV types 1 and 2 and the sequence-divergent pathogen varicella zoster virus (VZV). T cells, controlled by TCR and HLA molecules that tolerate limited epitope amino acid variation, might cross-react between these microbes. We show that memory PBMC expansion with either HSV or VZV enriches for CD4 T cell lines that recognize the other agent at the whole-virus, protein, and peptide levels, consistent with bidirectional cross-reactivity. HSV-specific CD4 T cells recovered from HSV-seronegative persons can be explained, in part, by such VZV cross-reactivity. HSV-1-reactive CD8 T cells also cross-react with VZV-infected cells, full-length VZV proteins, and VZV peptides, as well as kill VZV-infected dermal fibroblasts. Mono- and cross-reactive CD8 T cells use distinct TCRB CDR3 sequences. Cross-reactivity to VZV is reconstituted by cloning and expressing TCRA/TCRB receptors from T cells that are initially isolated using HSV reagents. Overall, we define 13 novel CD4 and CD8 HSV-VZV cross-reactive epitopes and strongly imply additional cross-reactive peptide sets. Viral proteins can harbor both CD4 and CD8 HSV/VZV cross-reactive epitopes. Quantitative estimates of HSV/VZV cross-reactivity for both CD4 and CD8 T cells vary from 10 to 50%. Based on these findings, we hypothesize that host herpesvirus immune history may influence the pathogenesis and clinical outcome of subsequent infections or vaccinations for related pathogens and that cross-reactive epitopes and TCRs may be useful for multi-alphaherpesvirus vaccine design and adoptive cellular therapy.
authors.affiliation: Department of Medicine, University of Washington, Seattle, USA.
authors.forename: Lichen
authors.initials: L
authors.lastname: Jing
authors.affiliation: Department of Medicine, University of Washington, Seattle, USA.
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Laing
authors.affiliation: Department of Medicine, University of Washington, Seattle, USA.
authors.forename: Lichun
authors.initials: L
authors.lastname: Dong
authors.affiliation: Department of Medicine, University of Washington, Seattle, USA.
authors.forename: Ronnie M
authors.initials: RM
authors.lastname: Russell
authors.affiliation: Department of Global Health, University of Washington, Seattle, USA.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Barlow
authors.affiliation: Max von Pettenkofer-Institute, Munich, Germany.|Division of Pathway Medicine, University of Edinburgh, United Kingdom.
authors.forename: Juergen G
authors.initials: JG
authors.lastname: Haas
authors.affiliation: Department of Medicine, University of Washington, Seattle, USA.
authors.forename: Meena S
authors.initials: MS
authors.lastname: Ramchandani
authors.affiliation: Department of Medicine, University of Washington, Seattle, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Johnston
authors.affiliation: Laboratory of Experimental Immunology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Soren
authors.initials: S
authors.lastname: Buus
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia.
authors.forename: Alec J
authors.initials: AJ
authors.lastname: Redwood
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, USA.
authors.forename: Katie D
authors.initials: KD
authors.lastname: White
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia.|Department of Medicine, Vanderbilt University School of Medicine, Nashville, USA.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Mallal
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia.|Department of Medicine, Vanderbilt University School of Medicine, Nashville, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Phillips
authors.affiliation: Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, USA.|Department of Laboratory Medicine, University of Washington, Seattle, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Posavad
authors.affiliation: Department of Medicine, University of Washington, Seattle, USA.|Department of Epidemiology, University of Washington, Seattle, USA.|Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, USA.|Department of Laboratory Medicine, University of Washington, Seattle, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Wald
authors.affiliation: Department of Medicine, University of Washington, Seattle, USA.|Department of Global Health, University of Washington, Seattle, USA.|Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, USA.|Department of Laboratory Medicine, University of Washington, Seattle, USA.|Benaroya Research Institute, Seattle, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Koelle
mesh_terms: D018138:Alphaherpesvirinae / Q000276:immunology*; D017951:Antigen Presentation / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003429:Cross Reactions / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006566:Herpesviridae Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology; D018258:Herpesvirus 2, Human / Q000276:immunology; D006801:Humans; D010455:Peptides / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014764:Viral Proteins / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins
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