Dominant recognition by human CD8+ cytotoxic T lymphocytes of dengue virus nonstructural proteins NS3 and NS1.2a
Division of Infectious Diseases and Immunology
Medical Subject Headings
Adult; CD8-Positive T-Lymphocytes; Cells, Cultured; Dengue Virus; Flavivirus; HLA Antigens; Histocompatibility Antigens Class I; Humans; *Immunodominant Epitopes; *Immunologic Memory; Lymphocyte Activation; RNA Helicases; Serine Endopeptidases; Serotyping; T-Lymphocytes, Cytotoxic; Viral Nonstructural Proteins; Viral Vaccines
Life Sciences | Medicine and Health Sciences
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.
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Citation: J Clin Invest. 1996 Oct 1;98(7):1684-91. Link to article on publisher's site
DOI of Published Version
The Journal of clinical investigation
Mathew, Anuja; Kurane, Ichiro; Rothman, Alan L.; Zeng, Lingling; Brinton, Margo A.; and Ennis, Francis A., "Dominant recognition by human CD8+ cytotoxic T lymphocytes of dengue virus nonstructural proteins NS3 and NS1.2a" (1996). GSBS Student Publications. 818.