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Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):E4256-63. doi: 10.1073/pnas.1505956112. Epub 2015 Jul 20.

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

Author information

1
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; daniela@liai.org.
2
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
3
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; Genetech Research Institute, Colombo, 00800, Sri Lanka;
4
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599.

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.

KEYWORDS:

CD4; HLA DR; T cell memory; cytotoxic; dengue virus

PMID:
26195744
PMCID:
PMC4534238
DOI:
10.1073/pnas.1505956112
[Indexed for MEDLINE]
Free PMC Article

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