FIGURE 3.

The role of CXCR3 and CXCR4 during arbovirus-induced encephalitis in mice. (1a) CXCR3⁺CD8⁺ T-cells migrate into the CNS in response to high levels of neuronal CXCL10. Loss of CXCR3 or its ligand CXCL10, or antagonizing this interaction (1b) prevents the migration of CD8⁺ T-cells into the CNS during WNV in mice. (2a) Virally infected neurons are the predominant source of CXCL10 in the CNS during WNV infection. (2b) Neuronal CXCL10 can engage CXCR3 that is upregulated on infected neurons and induce apoptosis. (2c) Blockade of CXCR3 with antagonists or CXCL10 neutralizing antibodies leads to the reduced binding of neuronal CXCL10 to neuronal CXCR3 and result in reduction of apoptosis and increased neuronal survival. (3a) During WNV infection, CXCR4⁺CD8⁺ T-cells migrate toward endothelial CXCL12, expressed on the inflamed cerebral endothelium. (3b) The interaction of CXCL12 and CXCR4 causes the CD8⁺ T-cells to be retained within the perivascular space. (3c,d) After blockade with the CXCR4 antagonist, AMD3100, the CD8⁺ T-cells are released and can migrate into the brain parenchyma where they promote clearance of WNV. Pathological steps are depicted in red; beneficial steps involved in increasing survival and improving disease outcome in the host are depicted in green. Gray arrows signify functions that are neither beneficial nor pathogenic.