title: Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects.
abstract: Human cytomegalovirus (HCMV) infections of immunocompetent hosts are characterized by a dynamic, life-long interaction in which host immune responses, particularly of T cells, restrain viral replication and prevent disease but do not eliminate the virus or preclude transmission. Because HCMV is among the largest and most complex of known viruses, the T cell resources committed to maintaining this balance have never been characterized completely. Here, using cytokine flow cytometry and 13,687 overlapping 15mer peptides comprising 213 HCMV open reading frames (ORFs), we found that 151 HCMV ORFs were immunogenic for CD4(+) and/or CD8(+) T cells, and that ORF immunogenicity was influenced only modestly by ORF expression kinetics and function. We further documented that total HCMV-specific T cell responses in seropositive subjects were enormous, comprising on average approximately 10% of both the CD4(+) and CD8(+) memory compartments in blood, whereas cross-reactive recognition of HCMV proteins in seronegative individuals was limited to CD8(+) T cells and was rare. These data provide the first glimpse of the total human T cell response to a complex infectious agent and will provide insight into the rules governing immunodominance and cross-reactivity in complex viral infections of humans.
authors.affiliation: Vaccine and Gene Therapy Institute, Department of Pathology, Oregon Health & Science University, Beaverton, 97006, USA.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Sylwester
authors.forename: Bridget L
authors.initials: BL
authors.lastname: Mitchell
authors.forename: John B
authors.initials: JB
authors.lastname: Edgar
authors.forename: Cara
authors.initials: C
authors.lastname: Taormina
authors.forename: Christian
authors.initials: C
authors.lastname: Pelte
authors.forename: Franziska
authors.initials: F
authors.lastname: Ruchti
authors.forename: Paul R
authors.initials: PR
authors.lastname: Sleath
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Grabstein
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Hosken
authors.forename: Florian
authors.initials: F
authors.lastname: Kern
authors.forename: Jay A
authors.initials: JA
authors.lastname: Nelson
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Picker
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003587:Cytomegalovirus / Q000235:genetics*; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007125:Immunogenetics; D007156:Immunologic Memory / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D016366:Open Reading Frames / Q000235:genetics; D010455:Peptides / Q000276:immunology; D012698:Serologic Tests
chemical_list: D010455:Peptides