Molecular Signatures of Dengue Virus-Specific IL-10/IFN-γ Co-producing CD4 T Cells and Their Association with Dengue Disease

Cell Rep. 2019 Dec 24;29(13):4482-4495.e4. doi: 10.1016/j.celrep.2019.11.098.

Abstract

Dengue virus (DENV) can cause diseases ranging from dengue fever (DF) to more severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Whether antiviral T cells contribute to the protection against or pathogenesis of severe disease is not well defined. Here, we identified antigen-specific IL-10+IFN-γ+ double-positive (DP) CD4 T cells during acute DENV infection. While the transcriptomic signatures of DP cells partially overlapped with those of cytotoxic and type 1 regulatory CD4 T cells, the majority of them were non-cytotoxic/Tr1 and included IL21, IL22, CD109, and CCR1. Although we observed a higher frequency of DP cells in DHF, the transcriptomic profile of DP cells was similar in DF and DHF, suggesting that DHF is not associated with the altered phenotypic or functional attributes of DP cells. Overall, this study revealed a DENV-specific DP cell subset in patients with acute dengue disease and argues against altered DP cells as a determinant of DHF.

Keywords: CD4 T cell; CyTOF; IFN-γ; IL-10; RNA-seq; acute dengue; dengue fever; dengue hemorrhagic fever; dengue virus; transcriptomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • Case-Control Studies
  • Dengue Virus / immunology*
  • Dengue Virus / pathogenicity
  • Female
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / immunology
  • Gene Expression Regulation / immunology*
  • Humans
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology*
  • Interleukin-10 / genetics
  • Interleukin-10 / immunology*
  • Interleukins / genetics
  • Interleukins / immunology
  • Male
  • Middle Aged
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology
  • Receptors, CCR1 / genetics
  • Receptors, CCR1 / immunology
  • Severe Dengue / genetics
  • Severe Dengue / immunology*
  • Severe Dengue / pathology
  • Severe Dengue / virology
  • Severity of Illness Index
  • Signal Transduction
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / virology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / virology
  • Transcriptome / immunology

Substances

  • Antigens, CD
  • CCR1 protein, human
  • CD109 protein, human
  • GPI-Linked Proteins
  • IL10 protein, human
  • Interleukins
  • Neoplasm Proteins
  • Receptors, CCR1
  • Interleukin-10
  • Interferon-gamma
  • interleukin-21
  • interleukin-22