Dengue virus infection elicits highly polarized CX3CR1⁺ cytotoxic CD4⁺ T cells associated with protective immunity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 31; pp. E4256 - E4263
• Main Authors: Weiskopf, Daniela, Bangs, Derek J., Sidney, John, Kolla, Ravi V., De Silva, Aruna D., de Silva, Aravinda M., Crotty, Shane, Peters, Bjoern, Sette, Alessandro
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 04-08-2015; National Acad Sciences
• Series: PNAS Plus
• Subjects: Adult; Alleles; Biological Sciences; CD4-Positive T-Lymphocytes - immunology; Cell Polarity; Cell Proliferation; CX3C Chemokine Receptor 1; Cytotoxicity; Cytotoxicity, Immunologic; Dengue - immunology; Dengue - virology; Dengue fever; Dengue virus; Dengue Virus - immunology; Female; Genotype & phenotype; Histocompatibility Antigens Class II - immunology; Humans; Immunity; Immunologic Memory; Lymphocyte Subsets - immunology; Male; Peptides - metabolism; Phenotype; PNAS Plus; Protein Binding; Receptors, Chemokine - metabolism; Species Specificity; T cell receptors; Viral infections; HLA DR; CD4; T cell memory; cytotoxic; dengue virus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1505956112

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.