title: Functional characterization of BK virus-specific CD4+ T cells with cytotoxic potential in seropositive adults.
abstract: BK polyomavirus (BKV) reactivation is associated with a failure of T cell immunity in kidney transplant patients, and may lead to BKV-associated nephropathy (BKVN) and loss of the allograft. BKV reactivation in hematopoietic stem cell transplant recipients is associated with hemorrhagic cystitis. We have investigated T cell responses to overlapping peptide mixtures corresponding to the whole BKV major T antigen (TAg) and major capsid protein (VP1) in peripheral blood mononuclear cell samples from a cohort of healthy BKV-seropositive subjects. The majority of these individuals possessed populations of both CD8(+) and CD4(+) T cells specific for these BKV antigens. After expansion in culture, the majority of the BKV-specific CD4(+) T cells, in addition to expressing CD40L (CD154), secreted both interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha, contained both granzyme A and granzyme B, and degranulated/mobilized CD107 in response to antigen-specific stimulation. These T cells thus represent potentially functional BKV-specific cytotoxic CD4(+) T lymphocytes. Secretion of both TNF-alpha and IFN-gamma by CD154(+)CD4(+) T cells on BKV-specific stimulation was associated with higher levels of granzyme B and a higher proportion of degranulating cells compared with CD154(+)CD4(+) T cells producing only IFN-gamma or neither cytokine. These healthy subjects also harbored populations of functional CD8(+) T cells specific for one or more of three newly defined HLA-A 02-restricted cytotoxic T lymphocyte epitopes within the BKV TAg as well as two HLA-A 02-restricted epitopes within the BKV VP1 we have previously described. The BKV-specific CD4(+) T cells characterized in this study may play a part in maintaining persistent memory T cell responses to the virus and thus contribute to the immune control of BKV in healthy individuals.
authors.affiliation: Laboratory of Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors.forename: Wendi
authors.initials: W
authors.lastname: Zhou
authors.forename: Madeva
authors.initials: M
authors.lastname: Sharma
authors.forename: Joy
authors.initials: J
authors.lastname: Martinez
authors.forename: Tumul
authors.initials: T
authors.lastname: Srivastava
authors.forename: Don J
authors.initials: DJ
authors.lastname: Diamond
authors.forename: Wendy
authors.initials: W
authors.lastname: Knowles
authors.forename: Simon F
authors.initials: SF
authors.lastname: Lacey
mesh_terms: D000328:Adult; D000956:Antigens, Viral / Q000276:immunology; D001739:BK Virus / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D023201:CD40 Ligand / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D036022:Capsid Proteins / Q000276:immunology; D015550:Cell Degranulation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D053804:Granzymes / Q000032:analysis; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology; D027601:Polyomavirus Infections / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014412:Tumor Virus Infections / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D036022:Capsid Proteins; D018984:Epitopes, T-Lymphocyte; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D007371:Interferon-gamma; D053804:Granzymes