DEC-205+ DCs within the CNS critically modulate CD8+ T cell-mediated immunity against WNV encephalitis

Abstract

West Nile Virus (WNV) is the leading cause of mosquito-borne neuroinvasive disease in the United States. Upon entry into the central nervous system (CNS, WNV infects neurons causing neuronal injury and inflammation potentially resulting in long-term sequelae and death. In order to restrict viral replication and pathogenesis within the CNS, infiltrating virus-specific CD8+ T cells are dependent on dendritic cell (DC) mediated reactivation. While previous reports have shown that DCs rapidly accumulate within the CNS during infection, the subset necessary to induce T-cell mediated protection against WNV has not been clarified. Previously, DEC-205+ DCs were detected within the CNS during WNV infection. DEC-205, an endocytic receptor expressed on a subset of DCs, promotes cross-presentation and induction of anti-viral immunity. However, the specific role of DEC-205+ DCs in establishing immunity against WNV encephalitis is not known. We hypothesize that DEC-205+ DCs restrict WNV pathogenesis by activating anti-viral T cell immunity in the CNS. We show that DEC-205−/− mice have increased clinical disease and mortality compared to wild-type (WT) controls. The enhanced susceptibility of the DEC-205−/− mice arose from increased viral burden, however, this was associated with increased neuronal chemokine expression and numbers of infiltrating T cells and inflammatory myeloid cells. These results suggest that DEC-205+ DCs promote protective immune responses to CNS viral infection that limits immunopathology. These findings will uncover the mechanism by which DEC-205+ DCs modulate protective immune responses within the CNS in order to restrict a neurotropic viral infection.