Dominant recognition by human CD8+ cytotoxic T lymphocytes of dengue virus nonstructural proteins NS3 and NS1.2a

J Clin Invest. 1996 Oct 1;98(7):1684-91. doi: 10.1172/JCI118964.


A severe complication of dengue virus infection, dengue hemorrhagic fever (DHF), is hypothesized to be immunologically mediated and virus-specific cytotoxic T lymphocytes (CTLs) may trigger DHF. It is also likely that dengue virus-specific CTLs are important for recovery from dengue virus infections. There is little available information on the human CD8+ T cell responses to dengue viruses. Memory CD8+CTL responses were analyzed to determine the diversity of the T cell response to dengue virus and to identify immunodominant proteins using PBMC from eight healthy adult volunteers who had received monovalent, live-attenuated candidate vaccines of the four dengue serotypes. All the donors had specific T cell proliferation to dengue and to other flaviviruses that we tested. CTLs were generated from the stimulated PBMC of all donors, and in the seven donors tested, dengue virus-specific CD8+CTL activity was demonstrated. The nonstructural (NS3 and NS1.2a) and envelope (E) proteins were recognized by CD8+CTLs from six, five, and three donors, respectively. All donors recognized either NS3 or NS1.2a. In one donor who received a dengue 4 vaccine, CTL killing was seen in bulk culture against the premembrane protein (prM). This is the first demonstration of a CTL response against the prM protein. The CTL responses using the PBMC of two donors were serotype specific, whereas all other donors had serotype-cross-reactive responses. For one donor, CTLs specific for E, NS1.2a, and NS3 proteins were all HLA-B44 restricted. For three other donors tested, the potential restricting alleles for recognition of NS3 were B38, A24, and/or B62 and B35. These results indicate that the CD8+CTL responses of humans after immunization with one serotype of dengue virus are diverse and directed against a variety of proteins. The NS3 and NS1.2a proteins should be considered when designing subunit vaccines for dengue.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • CD8-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Dengue Virus / immunology*
  • Flavivirus / immunology
  • HLA Antigens
  • Histocompatibility Antigens Class I
  • Humans
  • Immunodominant Epitopes*
  • Immunologic Memory*
  • Lymphocyte Activation
  • RNA Helicases
  • Serine Endopeptidases
  • Serotyping
  • T-Lymphocytes, Cytotoxic / immunology*
  • Viral Nonstructural Proteins / immunology*
  • Viral Vaccines / immunology*


  • HLA Antigens
  • Histocompatibility Antigens Class I
  • Immunodominant Epitopes
  • NS3 protein, flavivirus
  • Viral Nonstructural Proteins
  • Viral Vaccines
  • Serine Endopeptidases
  • RNA Helicases