Identifying the cell type specific antiviral immune response against respiratory syncytial virus infection

Abstract

Respiratory syncytial virus (RSV) is the leading cause of respiratory viral infection in infants and children, yet little is known about the natural antiviral response to RSV. We investigated the cellular source and primary producer of type I interferon in RSV infection, and determined the signaling pathway activated by RSV to produce type I interferon and T cell priming. The cellular source and the primary producer of type I interferon were spatiotemporally tracked by interferon-$\beta$/YFP reporter mouse and analyzed by flow cytometry in RSV stimulated bone marrow cells and in vivo RSV infected lung cells. Results from in vitro RSV-stimulated BM cells revealed that RSV can induce interferon-$\beta$ production in plasmacytoid DCs (pDCs), monocytes, and neutrophils. Spatial and kinetic analysis of interferon-$\beta$ producing cells in RSV infection in vivo indicated that monocytes are rapidly recruited to the inflamed lung in the early phase of infection, and primarily produce interferon-$\beta$ via the MyD88-mediated pathway, but not the MAVS mediated pathway. Monocyte-ablated mice exhibited decreased interferon-Y-producing $CD8^+$ T cell frequency. Thus, these data indicate that monocytes play pivotal roles in the cytotoxic T cell response and are the primary type I interferon producers in RSV infection. We also investigated the differential role of dendritic cell subsets in adaptive T cell immunity in mucosal RSV infection. Our results suggested that $CD103^+$ conventional DCs (cDCs) were migrated to mediastinal lymph nodes in early period of RSV infection. In study using Batf3 deficient mice or Langerin-DTR mice, $CD103^+$ cDCs were required to induce proper CD4 T cell response and cytotoxic T cell response. Furthermore, pDC depleted mice impaired to prime cytotoxic T cell response. These findings reveals that the host immune system need pDCs as well as $CD103^+$ cDCs to induce antiviral adaptive T cell response against RSV infection.