title: Discovering naturally processed antigenic determinants that confer protective T cell immunity.
abstract: CD8+ T cells (TCD8) confer protective immunity against many infectious diseases, suggesting that microbial TCD8 determinants are promising vaccine targets. Nevertheless, current T cell antigen identification approaches do not discern which epitopes drive protective immunity during active infection - information that is critical for the rational design of TCD8-targeted vaccines. We employed a proteomics-based approach for large-scale discovery of naturally processed determinants derived from a complex pathogen, vaccinia virus (VACV), that are presented by the most frequent representatives of four major HLA class I supertypes. Immunologic characterization revealed that many previously unidentified VACV determinants were recognized by smallpox-vaccinated human peripheral blood cells in a variegated manner. Many such determinants were recognized by HLA class I-transgenic mouse immune TCD8 too and elicited protective TCD8 immunity against lethal intranasal VACV infection. Notably, efficient processing and stable presentation of immune determinants as well as the availability of naive TCD8 precursors were sufficient to drive a multifunctional, protective TCD8 response. Our approach uses fundamental insights into T cell epitope processing and presentation to define targets of protective TCD8 immunity within human pathogens that have complex proteomes, suggesting that this approach has general applicability in vaccine sciences.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Pavlo
authors.initials: P
authors.lastname: Gilchuk
authors.forename: Charles T
authors.initials: CT
authors.lastname: Spencer
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Conant
authors.forename: Timothy
authors.initials: T
authors.lastname: Hill
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Gray
authors.forename: Xinnan
authors.initials: X
authors.lastname: Niu
authors.forename: Mu
authors.initials: M
authors.lastname: Zheng
authors.forename: John J
authors.initials: JJ
authors.lastname: Erickson
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Boyd
authors.forename: K Jill
authors.initials: KJ
authors.lastname: McAfee
authors.forename: Carla
authors.initials: C
authors.lastname: Oseroff
authors.forename: Sine R
authors.initials: SR
authors.lastname: Hadrup
authors.forename: Jack R
authors.initials: JR
authors.lastname: Bennink
authors.forename: William
authors.initials: W
authors.lastname: Hildebrand
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Edwards
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
authors.forename: John V
authors.initials: JV
authors.lastname: Williams
authors.forename: Søren
authors.initials: S
authors.lastname: Buus
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Ton N M
authors.initials: TN
authors.lastname: Schumacher
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Link
authors.forename: Sebastian
authors.initials: S
authors.lastname: Joyce
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000941:Antigens / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D000939:Epitopes / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology; D010641:Phenotype; D013601:T-Lymphocytes / Q000166:cytology*; D014616:Vaccinia virus / Q000378:metabolism*
chemical_list: D000941:Antigens; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D010455:Peptides
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