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

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 (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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Alleles
  • CD4-Positive T-Lymphocytes / immunology*
  • CX3C Chemokine Receptor 1
  • Cell Polarity*
  • Cell Proliferation
  • Cytotoxicity, Immunologic*
  • Dengue / immunology*
  • Dengue / virology
  • Dengue Virus / immunology*
  • Female
  • Histocompatibility Antigens Class II / immunology
  • Humans
  • Immunity*
  • Immunologic Memory
  • Lymphocyte Subsets / immunology
  • Male
  • Peptides / metabolism
  • Phenotype
  • Protein Binding
  • Receptors, Chemokine / metabolism*
  • Species Specificity


  • CX3C Chemokine Receptor 1
  • CX3CR1 protein, human
  • Histocompatibility Antigens Class II
  • Peptides
  • Receptors, Chemokine