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In this study, cells infiltrating the brain tissue of JEV-infected mice were mainly identified as monocytic myeloid-derived suppressor cells (M-MDSCs), which subsequently differentiated into CD3<jats:sup>+<\/jats:sup>macrophages. Co-culture with T cells showed that both splenic M-MDSCs and brain infiltrated M-MDSCs isolated from JEV-infected mice inhibited T cell proliferation through ARG1 and iNOS. The splenectomy model revealed that JEV-induced M-MDSCs were mainly derived from bone marrow and migrated to the spleen and central nervous system (CNS). The results of the transcriptome analysis and IRF7-deficient mice indicated that the ZBP1-IRF7 signaling pathway stimulated by JEV RNA played a central role in the induction of M-MDSCs. M-MDSCs migrated into the CNS through the chemokine CCL2\/N-CCL2 derived from astrocytes and brain infiltrated M-MDSCs differentiated into CD3<jats:sup>+<\/jats:sup>macrophages through a mechanism mediated by M-CSF, IL-6 and IFN-\u03b3 in the brain microenvironment. These findings provide evidence for the mechanism that JEV regulates the differentiation of M-MDSCs and thereby exacerbates pathogenicity, which represents a potential therapeutic target for Japanese encephalitis (JE).<\/jats:p>","DOI":"10.3389\/fimmu.2022.838990","type":"journal-article","created":{"date-parts":[[2022,4,21]],"date-time":"2022-04-21T05:22:45Z","timestamp":1650518565000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["JEV Infection Induces M-MDSC Differentiation Into CD3+ Macrophages in the 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