title: Altered cytokine responses of dengue-specific CD4+ T cells to heterologous serotypes.
abstract: The interplay of different inflammatory cytokines induced during a dengue (DEN) virus infection plays a role in either protection or increased disease severity. We measured the frequencies and characterized the cytokine responses of DEN virus-specific memory CD4+ T cells in PBMC of six volunteers who received experimental live attenuated monovalent DEN vaccines. IFN-gamma and TNF-alpha responses to inactivated DEN Ags were detected in up to 0.54 and 1.17% of total circulating CD4+ T cells, respectively. Ags from the homologous serotype elicited the highest IFN-gamma response. The ratio of TNF-alpha- to IFN-gamma-producing CD4+ T cells was higher after stimulation with Ags from heterologous DEN serotypes. Peptide-specific CD4+ T cell frequencies of up to 0.089% were detected by direct staining using HLA class II tetramers. IFN-gamma and TNF-alpha responses to individual HLA class II-restricted peptide epitopes were detected in up to 0.05 and 0.27% of CD4+ T cells, respectively. Peptide sequences from the homologous serotype elicited a variety of cytokine response patterns. TNF-alpha- to IFN-gamma-positive CD4+ T cell ratios varied between peptides, but the ratio of the sum of responses was highest against heterologous serotypes. These results demonstrate epitope sequence-specific differences in T cell effector function. These patterns of effector responses may play a role in the immunopathogenesis of DEN hemorrhagic fever.
authors.affiliation: Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, Worcester, MA 01655, USA. Maloy_Mangada@acambis.com
authors.forename: Maloy M
authors.initials: MM
authors.lastname: Mangada
authors.forename: Alan L
authors.initials: AL
authors.lastname: Rothman
mesh_terms: D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D016207:Cytokines / Q000096:biosynthesis*; D003716:Dengue Virus / Q000145:classification / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006681:HLA-D Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D012697:Serine Endopeptidases / Q000032:analysis / Q000276:immunology; D012703:Serotyping; D013194:Staining and Labeling; D014613:Vaccines, Attenuated / Q000008:administration & dosage; D014765:Viral Vaccines / Q000008:administration & dosage; D000085242:Viral Proteases
chemical_list: D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D006681:HLA-D Antigens; D010446:Peptide Fragments; D012697:Serine Endopeptidases; D014613:Vaccines, Attenuated; D014765:Viral Vaccines; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases