講演要旨

Introduction. The dynamic interplay between an expanding virus and the concomitantly activated host immune response during the primary infection phase is critical for establishing a chronic infection. However the key sensors and regulatory mechanisms that ultimately move the virus-host dynamics towards virus persistence and immune system exhaustion are still poorly understood.
Objective. Identification of key elements during the establishment of viral persistence using the Lymphocytic Choriomeningitis Virus (LCMV) mouse model system.
Material and methods. C57BL6/J mice were infected with either a low dose (2×102 pfu) or a high dose (2×106 pfu) of LCMV-Docile strain to establish an acute or a persistent infection, respectively. Time-series transcriptomes from spleens were obtained by RNA-Seq, and were analyzed by weighted gene co-expression network analysis (WGCNA). At corresponding time points, virus loads were quantified by titration and immune cell subsets analyzed by flow cytometry. Conditional diphtheria toxin receptor-mediated cell knock-out was used to deplete Xcr1-positive dendritic cells (Xcr1+DC) in the chronic infection phase.
Results. WGCNA revealed modules of highly connected genes (hub genes) that represent the main biological pathways involved in acute versus persistent infection outcomes. Module comparisons from both infection outcomes showed a positive correlation between module size and preservation, indicating that few genes are involved in outcome-specific pathways. A chronic infection-specific module suggested an important biological role for the chemokine Xcl1 and responsive Xcr1+DC. Depletion of this cell population resulted in reduction of LCMV-specific CD8 T cells, increased virus loads and death.
Conclusions. Virus-specific CD8 T cell exhaustion during persistent LCMV infection is followed by an increase of crosspresenting Xcr1+DC in spleen that maintain a low level of cytotoxic effector cells and control virus loads to non-pathogenic levels. Immunotherapeutic strategies to boost Xcr1+DC-dependent T cell responses may present a mean to better control virus loads in persistent virus infections. ng novel opportunities for regulation of membrane and secretome proteins.