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

Abstract

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 CX 3 CR1 in the neuroinflammation induced by infection with Japanese encephalitis virus (JEV), a neurotrophic virus. Interestingly, CX 3 CR1 deficiency strongly enhanced susceptibility to JEV only after peripheral inoculation via footpad. By contrast, both CX 3 CR1 +/+ and CX 3 CR1 −/− mice showed comparable susceptibility to JEV following inoculation via intranasal and intraperitoneal routes. CX 3 CR1 −/− 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 CX 3 CR1 + CD11c + DCs appeared to enhance susceptibility of CX 3 CR1 −/− mice to JE after peripheral JEV inoculation. CX 3 CR1 ablation impaired the migration of CX 3 CR1 + 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, CX 3 CR1-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 + CX 3 CR1 + CD11c + DCs. Using biallelic functional CX 3 CR1 expression system, the functional expression of CX 3 CR1 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 CX 3 CR1 + CD11c + DCs was found to completely restore the resistance of CX 3 CR1 −/− 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 CX 3 CR1 ...

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