title: Memory CD8+ T cells from naturally acquired primary dengue virus infection are highly cross-reactive.
abstract: Cross-reactive memory T cells induced by primary infection with one of the four serotypes of dengue virus (DENV) are hypothesized to have an immunopathological function in secondary heterologous DENV infection. To define the T-cell response to heterologous serotypes, we isolated HLA-A(*)1101-restricted epitope-specific CD8(+) T-cell lines from primary DENV-immune donors. Cell lines exhibited marked cross-reactivity toward peptide variants representing the four DENV serotypes in tetramer binding and functional assays. Many clones responded similarly to homologous and heterologous serotypes with striking cross-reactivity between the DENV-1 and DENV-3 epitope variants. In vitro-stimulated T-cell lines consistently revealed a hierarchical induction of MIP-1β>degranulation>tumor necrosis factor α (TNFα)>interferon-γ (IFNγ), which depended on the concentration of agonistic peptide. Phosphoflow assays showed peptide dose-dependent phosphorylation of ERK1/2, which correlated with cytolysis, degranulation, and induction of TNFα and IFNγ, but not MIP-1β production. This is the first study to show significant DENV serotype-cross-reactivity of CD8(+) T cells after naturally acquired primary infection. We also show qualitatively different T-cell receptor signaling after stimulation with homologous and heterologous peptides. Our data support a model whereby the order of sequential DENV infections influences the immune response to secondary heterologous DENV infection, contributing to varying disease outcomes.
authors.affiliation: Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Friberg
authors.forename: Lynne
authors.initials: L
authors.lastname: Burns
authors.forename: Marcia
authors.initials: M
authors.lastname: Woda
authors.forename: Siripen
authors.initials: S
authors.lastname: Kalayanarooj
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Endy
authors.forename: Henry A F
authors.initials: HA
authors.lastname: Stephens
authors.forename: Sharone
authors.initials: S
authors.lastname: Green
authors.forename: Alan L
authors.initials: AL
authors.lastname: Rothman
authors.forename: Anuja
authors.initials: A
authors.lastname: Mathew
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D003429:Cross Reactions / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003715:Dengue / Q000276:immunology*; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015234:HLA-A Antigens / Q000276:immunology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D055815:Young Adult
chemical_list: D016207:Cytokines; D000939:Epitopes; D015234:HLA-A Antigens; D011948:Receptors, Antigen, T-Cell; D048049:Extracellular Signal-Regulated MAP Kinases