Abstract
Prior exposure to dengue virus (DENV) has a profound impact on the outcome of infection, which varies according to the interval between infections. Antibodies secreted by B cells and cytokines secreted by T cells are thought to contribute both to protective immunity against DENV and the pathogenesis of dengue disease. We analyzed peripheral blood mononuclear cells (PBMC) collected from Thai children over a 5-year prospective cohort study to define the dynamics of DENV-specific memory B and T cell responses and the impact of symptomatic or subclinical DENV infections. To measure B cell responses, PBMC were stimulated with IL-2 plus R848 and culture supernatants were tested for DENV-binding antibodies by ELISA. To measure T cell responses, PBMC were stimulated in dual-color ELISPOT assays with overlapping peptide pools of structural and non-structural proteins from the four DENV types. B cell responses were low to one or more DENV types prior to symptomatic infection and increased with reactivity to all four types after infection. Subjects who had a subclinical infection or who did not experience a DENV infection during the study period showed strong memory B cell responses to all four DENV types. T cell responses to DENV peptides demonstrated a cytokine hierarchy of IFN-γ > IL-2 > IFN-γ/IL-2. T cell responses were low or absent prior to secondary infections. The trends in T cell responses to DENV peptides over 3 year post-infection were highly variable, but subjects who had experienced a secondary DENV1 infection showed higher cytokine responses compared to subjects who had experienced a secondary DENV2 or subclinical infection. The longitudinal nature of our study demonstrates persistent memory B cell responses over years and a lasting but variable impact of secondary DENV infection on DENV-specific T cell responses.
Highlights
Immune memory is the hallmark of the adaptive immune response
Symptomatic dengue virus (DENV) infection was identified by febrile illness with laboratory confirmation of acute DENV infection defined by virus isolation and/or reverse transcriptase polymerase chain reaction (RT-PCR) in acute serum samples or seroconversion between acute and convalescent serum samples by IgM/IgG ELISA or hemagglutination inhibition (HAI) assay
We conducted a longitudinal analysis of memory B and T cell responses to DENV over a 5-year period in primary schoolchildren living in a dengue-endemic area
Summary
Immune memory is the hallmark of the adaptive immune response. The generation and persistence of memory B and T cells are key to protection against a subsequent infection with a pathogen and are the principles behind effective vaccination. Infection with a different DENV serotype (heterotypic secondary infection) is associated with an increased risk for DHF/DSS [4, 5, 13]. Both antibodies and T cells are hypothesized to contribute to this increased risk of severe disease through a variety of mechanisms, other data point to their ability to protect against severe DENV disease [14,15,16,17,18,19,20]. Evidence for a lower risk of severe disease during third or fourth DENV infections suggests that the cumulative effects of cross-reactive memory immune responses are beneficial [21,22,23]
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