West Nile Virus infected human dendritic cells induce natural killer T cells to produce anti-inflammatory cytokines (INC1P.406)

Abstract

Abstract West Nile Virus (WNV) infection is an emerging mosquito-borne zoonosis in the U.S. WNV initially replicates in keratinocytes and skin resident dendritic cells (DCs). Infected DCs in the skin or cutaneous lymph nodes are likely to interact with Invariant Natural Killer T cells (iNKTs), an innate effector cell type important for control of pathogen infections. Bidirectional interactions between DCs and iNKTs amplify the innate immune response to viral infections, thus controlling viral load and regulating adaptive immunity. iNKTs can be activated indirectly by inflammatory cytokines or stimulated by lipid antigens presented by CD1d. To assess the DC-iNKT interaction upon WNV infection, we infected human monocyte-derived DCs with WNV and studied their innate immune responses and their ability to activate isolated blood iNKTs. Infected DCs synthesized viral Envelope mRNA and protein, and upregulated costimulatory molecules but showed decreased expression of CD1d. Infected DCs secreted type I interferon, but not IL-12, IL-23, IL-18 or IL-10. Unexpectedly, the WNV-infected DCs stimulated human iNKTs to upregulate CD69 and produce IL-10, but not proinflammatory cytokines. In contrast, incubation of DCs with the TLR3 ligand polyIC did not lead to iNKT IL-10 production, suggesting that DC activation by viral RNA alone does not trigger this iNKT response. In sum, WNV-infected human DCs producing type I interferon induce iNKTs to secrete IL-10 but not proinflammatory cytokines.