title: Dominance and diversity in the primary human CD4 T cell response to replication-competent vaccinia virus.
abstract: Vaccination with replication-competent vaccinia protects against heterologous orthopoxvirus challenge. CD4 T cells have essential roles helping functionally important Ab and CD8 antiviral responses, and contribute to the durability of vaccinia-specific memory. Little is known about the specificity, diversity, or dominance hierarchy of orthopoxvirus-specific CD4 T cell responses. We interrogated vaccinia-reactive CD4 in vitro T cell lines with vaccinia protein fragments expressed from an unbiased genomic library, and also with a panel of membrane proteins. CD4 T cells from three primary vaccinees reacted with 44 separate antigenic regions in 35 vaccinia proteins, recognizing 8 to 20 proteins per person. The integrated responses to the Ags that we defined accounted for 49 to 81% of the CD4 reactivity to whole vaccinia Ag. Individual dominant Ags drove up to 30% of the total response. The gene F11L-encoded protein was immunodominant in two of three subjects and is fragmented in a replication-incompetent vaccine candidate. The presence of protein in virions was strongly associated with CD4 antigenicity. These findings are consistent with models in which exogenous Ag drives CD4 immunodominance, and provides tools to investigate the relationship between Ab and CD4 T cell specificity for complex pathogens.
authors.affiliation: Department of Medicine, University of Washington, Seattle 98101, USA.
authors.forename: Lichen
authors.initials: L
authors.lastname: Jing
authors.forename: Tiana M
authors.initials: TM
authors.lastname: Chong
authors.forename: Benjamin
authors.initials: B
authors.lastname: Byrd
authors.forename: Christopher L
authors.initials: CL
authors.lastname: McClurkan
authors.forename: Jay
authors.initials: J
authors.lastname: Huang
authors.forename: Brian T
authors.initials: BT
authors.lastname: Story
authors.forename: Karissa M
authors.initials: KM
authors.lastname: Dunkley
authors.forename: Lydia
authors.initials: L
authors.lastname: Aldaz-Carroll
authors.forename: Roselyn J
authors.initials: RJ
authors.lastname: Eisenberg
authors.forename: Gary H
authors.initials: GH
authors.lastname: Cohen
authors.forename: William W
authors.initials: WW
authors.lastname: Kwok
authors.forename: Allesandro
authors.initials: A
authors.lastname: Sette
authors.forename: David M
authors.initials: DM
authors.lastname: Koelle
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000914:Antibodies, Viral / Q000096:biosynthesis*; D000916:Antibody Diversity / Q000276:immunology*; D017951:Antigen Presentation / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D002478:Cells, Cultured; D002999:Clone Cells; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology* / Q000378:metabolism; D008969:Molecular Sequence Data; D014616:Vaccinia virus / Q000276:immunology* / Q000502:physiology; D014779:Virus Replication / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes