Effects of Human Respiratory Syncytial Virus, Metapneumovirus, Parainfluenza Virus 3 and Influenza Virus on CD4+ T Cell Activation by Dendritic Cells

BACKGROUND: Human 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 FINDINGS: We 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, SIGNIFICANCE: Understanding 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

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Interleukin-6−174 and Tumor Necrosis Factor α−308 Polymorphisms Enhance Cytokine Production by Human Macrophages Exposed to Respiratory Viruses

Interleukin-6−174 (IL-6−174) and tumor necrosis factor α−308 (TNFα−308) are high-cytokine-producing genotypes that are known to increase the susceptibility to infectious diseases, but their influence on cytokine production induced by respiratory viruses is unknown. We exposed human monocyte-derived macrophages from IL-6−174, TNFα−308, and normal genotype donors to different respiratory viruses. Respiratory syncytial virus (RSV) stimulation was associated with higher IL-6 concentrations in IL-6−174 donors than in normal donors (P = 0.015); 2 of 7 (29%) polymorphic donors were poor responders compared with 6 of 7 (86%) normal donors (P = 0.002). Adenovirus, influenza virus, and RSV stimulations were associated with higher TNFα concentrations in TNFα−308 donors than in normal donors (P = 0.03, <0.01, <0.01). A similar trend was seen with rhinovirus stimulation, but this was not significant. These results show that IL-6−174 and TNFα−308 gene polymorphisms lead to enhanced production of the respective cytokines when exposed to specific respiratory viruses. This, in turn, may influence the susceptibility to, severity of, and recovery from respiratory virus infections, or influence the immune response to and reactogenicity of viral vaccines