title: Surface phenotype and functionality of WNV specific T cells differ with age and disease severity.
abstract: West Nile virus (WNV) infection can result in severe neuroinvasive disease, particularly in persons with advanced age. As rodent models demonstrate that T cells play an important role in limiting WNV infection, and strong T cell responses to WNV have been observed in humans, we postulated that inadequate antiviral T cell immunity was involved in neurologic sequelae and the more severe outcomes associated with age. We previously reported the discovery of six HLA-A*0201 restricted WNV peptide epitopes, with the dominant T cell targets in naturally infected individuals being SVG9 (Env) and SLF9 (NS4b). Here, memory phenotype and polyfunctional CD8+ T cell responses to these dominant epitopes were assessed in 40 WNV seropositive patients displaying diverse clinical symptoms. The patients' PBMC were stained with HLA-I multimers loaded with the SVG9 and SLF9 epitopes and analyzed by multicolor flow cytometry. WNV-specific CD8+ T cells were found in peripheral blood several months post infection. The number of WNV-specific T cells in older individuals was the same, if not greater, than in younger members of the cohort. WNV-specific T cells were predominantly monofunctional for CD107a, MIP-1β, TNFα, IL-2, or IFNγ. When CD8+ T cell responses were stratified by disease severity, an increased number of terminally differentiated, memory phenotype (CD45RA+ CD27- CCR7- CD57+) T cells were detected in patients suffering from viral neuroinvasion. In conclusion, T cells of a terminally differentiated/cytolytic profile are associated with neuroinvasion and, regardless of age, monofunctional T cells persist following infection. These data provide the first indication that particular CD8+ T cell phenotypes are associated with disease outcome following WNV infection.
authors.affiliation: Department of Infectious Diseases and Microbiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Paolo
authors.initials: P
authors.lastname: Piazza
authors.forename: Curtis P
authors.initials: CP
authors.lastname: McMurtrey
authors.forename: Alina
authors.initials: A
authors.lastname: Lelic
authors.forename: Robert L
authors.initials: RL
authors.lastname: Cook
authors.forename: Rachel
authors.initials: R
authors.lastname: Hess
authors.forename: Eric
authors.initials: E
authors.lastname: Yablonsky
authors.forename: Luann
authors.initials: L
authors.lastname: Borowski
authors.forename: Mark B
authors.initials: MB
authors.lastname: Loeb
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Bramson
authors.forename: William H
authors.initials: WH
authors.lastname: Hildebrand
authors.forename: Charles R
authors.initials: CR
authors.lastname: Rinaldo
mesh_terms: D000367:Age Factors; D018959:CD57 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry; D015234:HLA-A Antigens / Q000235:genetics; D006801:Humans; D007156:Immunologic Memory; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008024:Ligands; D010641:Phenotype; D054400:Receptors, CCR7 / Q000378:metabolism; D013601:T-Lymphocytes / Q000821:virology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000096:biosynthesis; D014901:West Nile Fever / Q000473:pathology / Q000821:virology; D014902:West Nile virus / Q000235:genetics*
chemical_list: C515370:CCR7 protein, human; D018959:CD57 Antigens; D000939:Epitopes; D015234:HLA-A Antigens; D008024:Ligands; D054400:Receptors, CCR7; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D017493:Leukocyte Common Antigens