title: Identification of cross-reactive norovirus CD4+ T cell epitopes.
abstract: Immune responses and the components of protective immunity following norovirus infection in humans are poorly understood. Although antibody responses following norovirus infection have been partially characterized, T cell responses in humans remain largely undefined. In contrast, T cells have been shown to be essential for viral clearance of mouse norovirus (MNV) infection. In this paper, we demonstrate that CD4(+) T cells secrete gamma interferon (IFN-gamma) in response to stimulation with MNV virus-like particles (VLPs) after MNV infection, supporting earlier reports for norovirus-infected mice and humans. Utilizing this model, we immunized mice with alphavirus vectors (Venezuelan equine encephalitis [VEE] virus replicon particles [VRPs]) expressing Norwalk virus (NV) or Farmington Hills virus (FH) virus-like particles to evaluate T cell epitopes shared between human norovirus strains. Stimulation of splenocytes from norovirus VRP-immunized mice with overlapping peptides from complete libraries of the NV or FH capsid proteins revealed specific amino acid sequences containing T cell epitopes that were conserved within genoclusters and genogroups. Immunization with heterologous norovirus VRPs resulted in specific cross-reactive IFN-gamma secretion profiles following stimulation with NV and FH peptides in the mouse. Identification of unique strain-specific and cross-reactive epitopes may provide insight into homologous and heterologous T cell-mediated norovirus immunity and provide a platform for the study of norovirus-induced cellular immunity in humans.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine University of North Carolina at Chapel Hill, North Carolina 27599-7435, USA.
authors.forename: Anna D
authors.initials: AD
authors.lastname: LoBue
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Lindesmith
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Baric
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D017250:Caliciviridae Infections / Q000276:immunology* / Q000821:virology; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D019143:Evolution, Molecular; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D029322:Norovirus / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D016415:Sequence Alignment; D013045:Species Specificity; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: D036022:Capsid Proteins; D018984:Epitopes, T-Lymphocyte; D007371:Interferon-gamma