title: Epitope specificity delimits the functional capabilities of vaccine-induced CD8 T cell populations.
abstract: Despite progress toward understanding the correlates of protective T cell immunity in HIV infection, the optimal approach to Ag delivery by vaccination remains uncertain. We characterized two immunodominant CD8 T cell populations generated in response to immunization of BALB/c mice with a replication-deficient adenovirus serotype 5 vector expressing the HIV-derived Gag and Pol proteins at equivalent levels. The Gag-AI9/H-2K(d) epitope elicited high-avidity CD8 T cell populations with architecturally diverse clonotypic repertoires that displayed potent lytic activity in vivo. In contrast, the Pol-LI9/H-2D(d) epitope elicited motif-constrained CD8 T cell repertoires that displayed lower levels of physical avidity and lytic activity despite equivalent measures of overall clonality. Although low-dose vaccination enhanced the functional profiles of both epitope-specific CD8 T cell populations, greater polyfunctionality was apparent within the Pol-LI9/H-2D(d) specificity. Higher proportions of central memory-like cells were present after low-dose vaccination and at later time points. However, there were no noteworthy phenotypic differences between epitope-specific CD8 T cell populations across vaccine doses or time points. Collectively, these data indicate that the functional and phenotypic properties of vaccine-induced CD8 T cell populations are sensitive to dose manipulation, yet constrained by epitope specificity in a clonotype-dependent manner.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Brenna J
authors.initials: BJ
authors.lastname: Hill
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Darrah
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Zachary
authors.initials: Z
authors.lastname: Ende
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: David R
authors.initials: DR
authors.lastname: Ambrozak
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Kylie M
authors.initials: KM
authors.lastname: Quinn
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Sam
authors.initials: S
authors.lastname: Darko
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom;
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.affiliation: Faculty of Medical and Veterinary Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom;
authors.forename: Linda
authors.initials: L
authors.lastname: Wooldridge
authors.affiliation: Mathematics Institute, University of Warwick, Coventry CV4 7AL, United Kingdom;
authors.forename: Hugo A
authors.initials: HA
authors.lastname: van den Berg
authors.affiliation: Computational Biology Group, Centre for Vascular Research, University of New South Wales, Kensington 2052, New South Wales, Australia;
authors.forename: Vanessa
authors.initials: V
authors.lastname: Venturi
authors.affiliation: INSERM, U1135, Centre d'Immunologie et des Maladies Infectieuses, F-75013 Paris, France; and Centre d'Immunologie et des Maladies Infectieuses, Sorbonne Universités, Université Pierre et Marie Curie (Université Paris 06), CR7, F-75013 Paris, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Larsen
authors.affiliation: Computational Biology Group, Centre for Vascular Research, University of New South Wales, Kensington 2052, New South Wales, Australia;
authors.forename: Miles P
authors.initials: MP
authors.lastname: Davenport
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Robert A
authors.initials: RA
authors.lastname: Seder
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom; ddouek@mail.nih.gov priced6@cardiff.ac.uk.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; ddouek@mail.nih.gov priced6@cardiff.ac.uk.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
mesh_terms: D016915:AIDS Vaccines; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D005260:Female; D005822:Genetic Vectors; D006183:H-2 Antigens / Q000378:metabolism; D064532:Histocompatibility Antigen H-2D / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000378:metabolism*; D007156:Immunologic Memory; D051379:Mice; D008807:Mice, Inbred BALB C; D014611:Vaccination; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D016915:AIDS Vaccines; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D064532:Histocompatibility Antigen H-2D; D016056:Immunodominant Epitopes; D054301:gag Gene Products, Human Immunodeficiency Virus; D054302:pol Gene Products, Human Immunodeficiency Virus