title: Dengue virus infection elicits highly polarized CX3CR1+ cytotoxic CD4+ T cells associated with protective immunity.
abstract: Dengue virus (DENV) is a rapidly spreading pathogen with unusual pathogenesis, and correlates of protection from severe dengue disease and vaccine efficacy have not yet been established. Although DENV-specific CD8(+) T-cell responses have been extensively studied, the breadth and specificity of CD4(+) T-cell responses remains to be defined. Here we define HLA-restricted CD4(+) T-cell epitopes resulting from natural infection with dengue virus in a hyperepidemic setting. Ex vivo flow-cytometric analysis of DENV-specific CD4(+) T cells revealed that the virus-specific cells were highly polarized, with a strong bias toward a CX3CR1(+) Eomesodermin(+) perforin(+) granzyme B(+) CD45RA(+) CD4 CTL phenotype. Importantly, these cells correlated with a protective HLA DR allele, and we demonstrate that these cells have direct ex vivo DENV-specific cytolytic activity. We speculate that cytotoxic dengue-specific CD4(+) T cells may play a role in the control of dengue infection in vivo, and this immune correlate may be a key target for dengue virus vaccine development.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; daniela@liai.org.
authors.forename: Daniela
authors.initials: D
authors.lastname: Weiskopf
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Bangs
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Ravi V
authors.initials: RV
authors.lastname: Kolla
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; Genetech Research Institute, Colombo, 00800, Sri Lanka;
authors.forename: Aruna D
authors.initials: AD
authors.lastname: De Silva
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599.
authors.forename: Aravinda M
authors.initials: AM
authors.lastname: de Silva
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
mesh_terms: D000328:Adult; D000483:Alleles; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D000073883:CX3C Chemokine Receptor 1; D016764:Cell Polarity; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D003715:Dengue / Q000276:immunology* / Q000821:virology; D003716:Dengue Virus / Q000276:immunology*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007109:Immunity; D007156:Immunologic Memory; D016131:Lymphocyte Subsets / Q000276:immunology; D008297:Male; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D019707:Receptors, Chemokine / Q000378:metabolism*; D013045:Species Specificity
chemical_list: D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D019707:Receptors, Chemokine
keywords: CD4; HLA DR; T cell memory; cytotoxic; dengue virus