title: Clonotypic composition of the CD4+ T cell response to a vectored retroviral antigen is determined by its speed.
abstract: The mechanisms whereby different vaccines may expand distinct Ag-specific T cell clonotypes or induce disparate degrees of protection are incompletely understood. We found that several delivery modes of a model retroviral Ag, including natural infection, preferentially expanded initially rare high-avidity CD4(+) T cell clonotypes, known to mediate protection. In contrast, the same Ag vectored by human adenovirus serotype 5 induced clonotypic expansion irrespective of avidity, eliciting a predominantly low-avidity response. Nonselective clonotypic expansion was caused by relatively weak adenovirus serotype 5-vectored Ag presentation and was reproduced by replication-attenuated retroviral vaccines. Mechanistically, the potency of Ag presentation determined the speed and, consequently, completion of the CD4(+) T cell response. Whereas faster completion retained the initial advantage of high-avidity clonotypes, slower completion permitted uninhibited accumulation of low-avidity clonotypes. These results highlighted the importance of Ag presentation patterns in determining the clonotypic composition of vaccine-induced T cell responses and ultimately the efficacy of vaccination.
authors.affiliation: Division of Immunoregulation, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom;
authors.forename: Georgina
authors.initials: G
authors.lastname: Thorborn
authors.affiliation: Division of Immunoregulation, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom;
authors.forename: Mickaël J
authors.initials: MJ
authors.lastname: Ploquin
authors.affiliation: Division of Immunoregulation, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom;
authors.forename: Urszula
authors.initials: U
authors.lastname: Eksmond
authors.affiliation: Division of Immunoregulation, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom;
authors.forename: Rebecca
authors.initials: R
authors.lastname: Pike
authors.affiliation: Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen 45147, Germany;
authors.forename: Wibke
authors.initials: W
authors.lastname: Bayer
authors.affiliation: Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen 45147, Germany;
authors.forename: Ulf
authors.initials: U
authors.lastname: Dittmer
authors.affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840;
authors.forename: Kim J
authors.initials: KJ
authors.lastname: Hasenkrug
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98195; and.
authors.forename: Marion
authors.initials: M
authors.lastname: Pepper
authors.affiliation: Division of Immunoregulation, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom; Department of Medicine, Faculty of Medicine, Imperial College London, London W2 1PG, United Kingdom gkassio@nimr.mrc.ac.uk.
authors.forename: George
authors.initials: G
authors.lastname: Kassiotis
mesh_terms: D000818:Animals; D000915:Antibody Affinity / Q000276:immunology*; D017951:Antigen Presentation / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D060966:Clonal Selection, Antigen-Mediated / Q000276:immunology*; D005622:Friend murine leukemia virus / Q000276:immunology*; D020869:Gene Expression Profiling; D015686:Gene Products, env / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D053262:Receptors, OX40 / Q000235:genetics; D014765:Viral Vaccines / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D015686:Gene Products, env; D011948:Receptors, Antigen, T-Cell; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; D014765:Viral Vaccines