DEC-205-expressing dendritic cells inhibit T cell responses during West Nile Virus encephalitis in the central nervous system

Abstract

Abstract West Nile Virus (WNV), a neurotropic flavivirus, is the leading cause of mosquito-borne neuroinvasive disease in the U.S. Recent studies show that dysfunctional T cell responses correlate with severe disease in both humans and mice. Dendritic cells (DCs) are critical for reactivating antiviral CD8+ T cell responses in the CNS that are required to mitigate viral encephalitis. Previous reports have shown that CNS-localized DEC-205+ DCs accumulate within the CNS during WNV encephalitis; however, their specific role in programming T cell immunity remains poorly understood. DEC-205, an endocytic receptor expressed by DC subsets can promote either antigen-specific effector T cell activation or immunological T cell tolerance. Using a mouse model of WNV encephalitis, we demonstrate that DEC-205−/− mice exhibit enhanced clinical signs of disease and increased mortality compared to WT controls. The enhanced susceptibility in DEC-205−/− mice arose from an increased viral burden with the CNS; however, this was associated with increased inflammatory myeloid, CD4+, and CD8+ T cell infiltrates. In addition, expression of activation markers CD25 and CD44 increased while CD69 levels decreased within the DEC-205−/− mice compared with their WT counterparts. CD69 expression has been shown to be associated with regulatory T cells. To confirm the immunomodulatory role of DEC-205, we will measure CD4+ regulatory T cell frequencies within the CNS of DEC-205−/− and WT animals following WNV infection. Taken together, these data suggest that DEC-205 critically regulates WNV pathogenesis and neuroinvasive disease by limiting immune-mediated pathology in the CNS following WNV infection. Supported by grants from NIH (SC3GM130472).