title: The Cellular Localization of Human Cytomegalovirus Glycoprotein Expression Greatly Influences the Frequency and Functional Phenotype of Specific CD4+ T Cell Responses.
abstract: CMV infection is a significant cause of morbidity and mortality in immunocompromised individuals, and the development of a vaccine is of high priority. Glycoprotein B (gB) is a leading vaccine candidate but the glycoprotein H (gH) pentameric complex is now recognized as the major target for neutralizing Abs. However, little is known about the T cell immune response against gH and glycoprotein L (gL) and this is likely to be an important attribute for vaccine immunogenicity. In this study, we examine and contrast the magnitude and phenotype of the T cell immune response against gB, gH, and gL within healthy donors. gB-specific CD4(+) T cells were found in 95% of donors, and 29 epitopes were defined with gB-specific response sizes ranging from 0.02 to 2.88% of the CD4(+) T cell pool. In contrast, only 20% of donors exhibited a T cell response against gH or gL. Additionally, gB-specific CD4(+) T cells exhibited a more cytotoxic phenotype, with high levels of granzyme B expression. Glycoproteins were effectively presented following delivery to APCs but only gB-derived epitopes were presented following endogenous synthesis. gB expression was observed exclusively within vesicular structures colocalizing with HLA-DM whereas gH was distributed evenly throughout the cytoplasm. Grafting of the C-terminal domain from gB onto gH could not transfer this pattern of presentation. These results reveal that gB is a uniquely immunogenic CMV glycoprotein and this is likely to reflect its unique pattern of endogenous Ag presentation. Consideration may be required toward mechanisms that boost cellular immunity to gH and gL within future subunit vaccines.
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, United Kingdom; and a.pachnio@bham.ac.uk p.moss@bham.ac.uk.
authors.forename: Annette
authors.initials: A
authors.lastname: Pachnio
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, United Kingdom; and.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zuo
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, United Kingdom; and.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Ryan
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, United Kingdom; and.
authors.forename: Jusnara
authors.initials: J
authors.lastname: Begum
authors.affiliation: School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, United Kingdom; and University Hospitals Birmingham National Health Service Foundation Trust, Birmingham B15 2TH, United Kingdom.
authors.forename: Paul A H
authors.initials: PA
authors.lastname: Moss
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D022482:Cytomegalovirus Vaccines / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D053804:Granzymes; D006801:Humans; D007111:Immunity, Cellular; D008297:Male; D008875:Middle Aged; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D022482:Cytomegalovirus Vaccines; D018984:Epitopes, T-Lymphocyte; D014759:Viral Envelope Proteins; C509213:GZMB protein, human; D053804:Granzymes