XCL1 facilitates the interaction with CD8+ T-cells and XCR1+ DCs within the Cervical Lymph Nodes during WNV encephalitis

Abstract

Abstract West Nile Virus (WNV), a neurotropic flavivirus, causes encephalitis, especially in elderly and immunocompromised individuals. Previous studies have demonstrated that CNS-localized dendritic cells (DCs) protect against WNV neuroinvasive disease by establishing antiviral T-cell responses in the CNS. In this study, we investigated the role of the XCL1-XCR1 interaction since its primary function is to facilitate DC-mediated CD8+ T cell immunity. XCL1, also known as lymphotactin, is expressed by various immune cells, including activated CD8+ T cells, and binds to XCR1, a chemokine receptor expressed predominately by a subset of DCs. Following subcutaneous infection with WNV, XCL1 expression increased within the CNS on day 6 post-infection after local viral replication began. In contrast, the expression of its receptor, XCR1, increased by day 9 post-infection in wild-type (WT) mice. We found that WNV-infected XCR1-deficient (XCR1−/−) mice demonstrated increased symptomatic disease and mortality in conjunction with the increased viral burden correlating with decreased CD8+ T-cell recruitment and activation at day 12 post-infection in the CNS compared with their WT counterparts. We found that XCR1+ DCs were present in the cervical lymph nodes at days 6 and 9 post-infection and in the CNS at day 12 post-infection. Taken together, these results suggest that the XCL1-XCR1 interaction promotes viral clearance and protection against WNV neuroinvasive disease. NIH-SC3GM130472