Abstract
BackgroundHuman respiratory syncytial virus (HRSV), and to a lesser extent human metapneumovirus (HMPV) and human parainfluenza virus type 3 (HPIV3), re-infect symptomatically throughout life without antigenic change, suggestive of incomplete immunity. One causative factor is thought to be viral interference with dendritic cell (DC)-mediated stimulation of CD4+ T cells.Methodology, Principal FindingsWe infected human monocyte-derived DC with purified HRSV, HMPV, HPIV3, or influenza A virus (IAV) and compared their ability to induce activation and proliferation of autologous CD4+ T cells in vitro. IAV was included because symptomatic re-infection without antigenic change is less frequent, suggesting that immune protection is more complete and durable. We examined virus-specific memory responses and superantigen-induced responses by multiparameter flow cytometry. Live virus was more stimulatory than inactivated virus in inducing DC-mediated proliferation of virus-specific memory CD4+ T cells, suggesting a lack of strong suppression by live virus. There were trends of increasing proliferation in the order: HMPV<HRSV<HPIV3<IAV, and greater production of interferon-γ and tumor necrosis factor-α by proliferating cells in response to IAV, but differences were not significant. Exposure of DC to HRSV, HPIV3, or IAV reduced CD4+ T cell proliferation in response to secondary stimulus with superantigen, but the effect was transitory and greatest for IAV. T cell cytokine production was similar, with no evidence of Th2 or Th17 skewing.Conclusions, SignificanceUnderstanding the basis for the ability of HRSV in particular to symptomatically re-infect without significant antigenic change is of considerable interest. The present results show that these common respiratory viruses are similar in their ability to induce DC to activate CD4+ T cells. Thus, the results do not support the common model in which viral suppression of CD4+ T cell activation and proliferation by HRSV, HMPV, and HPIV3 is a major factor in the difference in re-infectability compared to IAV.
Highlights
Human respiratory syncytial virus (HRSV) is the most important viral agent of serious pediatric respiratory tract disease worldwide [1,2,3,4,5]
Comparison of the ability of human MDDC stimulated with rHRSV, rHMPV, rHPIV3, or influenza A virus (IAV) to induce proliferation of autologous CD4+ T cells
CD4 T cells were analyzed by flow cytometry to evaluate (i) proliferation, which was scored by dilution of CFSE dye that occurs with cell division (Figure 2), and (ii) cytokine production, measured by intracellular cytokine staining (Figure 3)
Summary
Human respiratory syncytial virus (HRSV) is the most important viral agent of serious pediatric respiratory tract disease worldwide [1,2,3,4,5]. The orthomyxovirus influenza A virus (IAV) causes serious disease in children and adults with the greatest burden of mortality being in the elderly [12] These common human respiratory viral pathogens share a tropism for the superficial epithelial cells of the respiratory tract, IAV appears to be much more cytopathic and efficiently infects underlying cells in the epithelium [13,14]. Serious infection with HRSV during infancy is associated with more severe sequelae compared to these other viruses, including increased airway reactivity that can persist through childhood as well as possible links to asthma. One causative factor is thought to be viral interference with dendritic cell (DC)-mediated stimulation of CD4+ T cells
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