In the absence of DEC-205, Enhanced inflammation in the CNS is Associated with Reduced numbers of IL-10-producing CD4+ T-cells During WNV encephalitis.

Abstract

Abstract West Nile Virus (WNV), a mosquito-borne single-stranded RNA flavivirus, can cause significant human morbidity and mortality. Previous studies have shown that dendritic cells (DCs) within the central nervous system (CNS) are required to reactivate antiviral effector T-cell responses that restrict WNV replication and limit immunopathology within the CNS. Among these DCs, one subset expressing DEC-205 accumulates within the CNS during WNV encephalitis. DEC-205, an endocytic receptor highly expressed on conventional DCs (cDCs), mediates the efficient processing and presentation of antigens in vivo, leading to either tolerance or immunity depending on DC maturation status, suggesting that DEC-205+ DCs play an immunoregulatory role in the CNS during WNV infection. However, the contributions of CNS-localized DEC-205+ DCs in programming WNV-specific T-cell immunity remains poorly understood. In preliminary experiments, WNV-infected DEC-205 −/−mice exhibited increased susceptibility to WNV infection, more severe clinical signs of disease, and loss of virologic control with early entry into the CNS despite the increased trafficking, activation, and effector response of CD4+ and CD8+ T cells. We found that this uncontrolled inflammatory response was associated with a lack of IL-10-expressing CD4+ T regulatory cell (T reg) expansion that occurs typically during acute WNV infection. Thus, the enhanced inflammatory response in the absence of DEC-205 was coupled with a failure to protect against WNV infection and neuroinvasive disease. Taken together, DEC-205-expressing DCs regulate the degree and balance of the antiviral immune response to WNV infection within the CNS by activating T regs. NIH SC3GM130472