EARLY MIGRATION AND ACTIVATION OF MIGRATORY DENDRITIC CELLS INDUCE ROBUST CD8⁺ T-CELL ACTIVATION FOLLOWING DERMAL BUT NOT RESPIRATORY ORTHOPOXVIRUS INFECTION

Antigen presentation to T-cells is a crucial step in adaptive immune response following viral infection. This process is initiated by professional antigen presenting cells (APC), primarily dendritic cells (DC) that sample the tissue for foreign antigens. Following virus infection, DC undergo maturation which result in promoted trafficking to the draining lymph node where they meet target lymphocytes and activate them.
In this study we used ectromelia virus – the mouse surrogate model for human smallpox, to study the differences between protective dermal infection and lethal respiratory infection. We show that cytotoxic T-cell response is crucial for protection provided by either primary dermal infection or by vaccination. We demonstrate that dermal infection induces fast and robust activation of CD8⁺ cytotoxic T-cells which precedes activation following respiratory infection by 2-3 days. This early activation is a result of fast activation of DC, upregulation of co-stimulatory factors and their migration from the site of infection to the draining lymph node where they encounter CD8⁺ cells. We further show that the skin migratory DC are better activators of CD8⁺ cells than lung migratory DC in the draining lymph nodes.
Using isolated subsets of DC, and knock-out mice, we show that in the skin both CD11b^highCD103^low and CD11b^lowCD103^high participate in early T-cell activation, while in the lung draining lymph node, only the CD11b^lowCD103^high subset is responsible for CD8⁺ T-cell activation. The efficient process in the skin was not dependent on Langerhans cells or Langerin⁺ DC.
Overall we show that efficient activation and migration of DC to the skin draining lymph node provides the efficient cellular response which is required for protection following virulent infection and thus make the skin a preferred site for smallpox vaccines.