title: Differential in vivo clearance and response to secondary heterologous infections by H2(b)-restricted dengue virus-specific CD8+ T cells.
abstract: Cytotoxic T lymphocytes (CTL) are hypothesized to play a role in clearance during primary dengue virus (DENV) infections, and contribute to immunopathology during secondary heterologous infections in humans. We previously reported skewed T-cell responses to secondary DENV infection in BALB/c (H-2(d)) mice, reproducing characteristics of human DENV infection. To set the stage for using widely available transgenic and knockout mice, we extended these studies to identify DENV-specific T-cell responses in C57BL/6 (H-2(b)) mice. We identified dominant CD8+ T-cell responses to H-2D(b)-restricted epitopes on the DENV NS4a (aa 249-265) and NS5 (aa 521-537) proteins. High frequencies of IFN-γ- and TNF-α-producing T cells directed at both epitopes were detected following primary infection with all four DENV serotypes, and were augmented by secondary DENV infections. In vivo cytotoxicity assays demonstrated rapid clearance of target cells pulsed with the NS4a peptide; in contrast, NS5 peptide-pulsed target cells were poorly cleared in vivo. These data characterize two H-2(b)-restricted T-cell epitopes displaying divergent in vivo function. These results should facilitate further studies of the in vivo effects of DENV-specific T cells, including the use of genetically modified mouse strains.
authors.affiliation: Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
authors.forename: Coreen M
authors.initials: CM
authors.lastname: Beaumier
authors.forename: Smita
authors.initials: S
authors.lastname: Jaiswal
authors.forename: Kim Y
authors.initials: KY
authors.lastname: West
authors.forename: Heather
authors.initials: H
authors.lastname: Friberg
authors.forename: Anuja
authors.initials: A
authors.lastname: Mathew
authors.forename: Alan L
authors.initials: AL
authors.lastname: Rothman
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D003715:Dengue / Q000276:immunology*; D003716:Dengue Virus / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006183:H-2 Antigens / Q000276:immunology; D064532:Histocompatibility Antigen H-2D; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D014409:Tumor Necrosis Factor-alpha; D017361:Viral Nonstructural Proteins; D007371:Interferon-gamma