Data_Sheet_1_Indispensable Role of CX3CR1+ Dendritic Cells in Regulation of Virus-Induced Neuroinflammation Through Rapid Development of Antiviral Immunity in Peripheral Lymphoid Tissues.PDF

A coordinated host immune response mediated via chemokine network plays a crucial role in boosting defense mechanisms against pathogenic infections. The speed of Ag presentation and delivery by CD11c⁺ dendritic cells (DCs) to cognate T cells in lymphoid tissues may decide the pathological severity of the infection. Here, we investigated the role of CX₃CR1 in the neuroinflammation induced by infection with Japanese encephalitis virus (JEV), a neurotrophic virus. Interestingly, CX₃CR1 deficiency strongly enhanced susceptibility to JEV only after peripheral inoculation via footpad. By contrast, both CX₃CR1^+/+ and CX₃CR1^−/− mice showed comparable susceptibility to JEV following inoculation via intranasal and intraperitoneal routes. CX₃CR1^−/− mice exhibited lethal neuroinflammation after JEV inoculation via footpad route, showing high mortality, morbidity, pro-inflammatory cytokine expression, and uncontrolled CNS-infiltration of peripheral leukocytes including Ly-6C^hi monocytes and Ly-6G^hi granulocytes. Furthermore, the absence of CX₃CR1⁺CD11c⁺ DCs appeared to enhance susceptibility of CX₃CR1^−/− mice to JE after peripheral JEV inoculation. CX₃CR1 ablation impaired the migration of CX₃CR1⁺CD11c⁺ DCs from JEV-inoculated sites to draining lymph nodes (dLNs), resulting in decreased NK cell activation and JEV-specific CD4⁺/CD8⁺ T-cell responses. However, CX₃CR1-competent mice showed rapid temporal expression of viral Ags in dLNs. Subsequently, JEV was rapidly cleared, with concomitant generation of antiviral NK cell activation and T-cell responses mediated by rapid migration of JEV Ag⁺CX₃CR1⁺CD11c⁺ DCs. Using biallelic functional CX₃CR1 expression system, the functional expression of CX₃CR1 on CD11c^hi DCs appeared to be essentially required for inducing rapid and effective responses of NK cell activation and Ag-specific CD4⁺ T cells in dLNs. Strikingly, adoptive transfer of CX₃CR1⁺CD11c⁺ DCs was found to completely restore the resistance of CX₃CR1^−/− recipients to JEV, as corroborated by the rapid delivery of JEV Ags in dLNs and attenuation of neuroinflammation in the CNS. Collectively, these results indicate that CX₃CR1⁺CD11c⁺ DCs play an important role in generating rapid and effective responses of antiviral NK cell activation and Ag-specific T cells after peripheral inoculation with the virus, thereby resulting in conferring resistance to viral infection by reducing the peripheral viral burden.