Two members of the IFN regulatory factor (IRF) family, IRF-3 and IRF-7, were shown to be the crucial players in transcriptional induction of IFN genes (1). IRF-3, which is expressed constitutively, is activated by virus-induced kinases (2, 3) and participates to the transcriptional induction of IFN-␤ and IFN-␣4 genes. The immediate-early IFNs produced by these genes signal through the IFN receptor in an autocrine and͞or paracrine fashion and up-regulate the transcription of many IFN-stimulated genes, notably of IRF-7. Upon viral infection of cells primed by IFN, IRF-7 and IRF-3, which are activated by the same kinases (2, 3), cooperate to induce the transcription of the other IFN-␣ genes (namely late IFNs) (4).In vitro, virtually any nucleated cell type can synthesize both IFN-␣ and IFN-␤. In vivo, however, for both humans (5, 6) and mice (7-9), the major IFN-producing cells were identified as being the plasmacytoid dendritic cells (pDCs). Large amounts of IFN are produced by human and mouse pDCs in response to a wide range of viruses, parasites, and bacteria.Many previous investigations focused on IFN-producing DCs in the periphery. In the central nervous system (CNS), however, DCs are reportedly limited to perivascular cells of peripheral origin (10), and pDCs were reported to be absent from the brain (11). Few data are available on cells responsible for IFN production in the CNS. In vitro experiments in primary cell cultures agree that astrocytes and microglia can produce type I IFNs but are conf licted regarding possible IFN production by neurons (12,13). A recent study showed that postmitotic neurons differentiated in vitro from the human NT2-N cell line were able to produce IFN-␤ in response to rabies virus infection (14). In vivo, very few studies tried to identify the IFN-producing cells in the CNS (15-18), and no general conclusion was reached.In this work, we used two neurotropic viruses, Theiler's virus, a murine picornavirus, and La Crosse virus, a bunyavirus, to investigate type I IFN production and response in the CNS in vivo. Theiler's virus (or Theiler's murine encephalomyelitis virus, TMEV) strains are divided into two subgroups according to the disease they produce. The neurovirulent strain (GDVII) causes an acute lethal encephalomyelitis, whereas the persistent strain (DA) causes a mild transient encephalitis that resolves and is followed by viral persistence in the spinal cord white matter (19). La Crosse virus (LACV) massively infects neurons and causes fulminant encephalitis. A mutant of LACV lacking a functional NSs gene (LACVdelNSs) was used in this study (20). Because the NSs gene product is an IFN antagonist (21), LACVdelNSs induces high amounts of IFN in infected cells. We used in situ hybridization (ISH) and double immunostaining to identify IFN-producing cells in the CNS. Our data show that IFN is largely produced by infected resident cells of the CNS. Interestingly, neurons accounted for a substantial proportion of IFN-producing cells. Neurons also responded to IFN by expressing Mx ...

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