In contrast to the limited information on IL-17 function during viral encephalitis, analysis of experimental autoimmune encephalitis (EAE) has revealed numerous insights into effector mechanisms as well selleck as crosstalk between Th1 and Th17 cells [16]. Although the inflammatory CNS disease multiple sclerosis and its animal model EAE were historically associated with a Th1 immune response [17,18], a pro-inflammatory role of IFN-�� was contradicted by substantially increased disease severity and mortality in mice deficient in IFN-�� (GKO) or the IFN-��R [19,20]. The correlation between increased EAE severity, enhanced Th17 responses and neutrophil infiltration into the CNS of GKO mice suggested that IFN-�� might be protective by inhibiting the Th17 response [21].

Although IL-17?/? mice are susceptible to EAE [22], adoptive transfer of polarized encephalitogenic CD4+ T cells support Th17 cells as detrimental participants in EAE [23,24]. However, the pathogenic mechanisms associated with Th17 cells remain an ongoing challenge and may involve multiple pathways. These include excessive CNS neutrophil infiltration and release of degrading enzymes, free radicals and pro-inflammatory cytokines, direct IL-17-mediated neuronal toxicity [25], and/or secretion of granulocyte macrophage colony-stimulating factor (GM-CSF) as the pathogenic effector molecule [26-28]. These data suggest that the balance between IFN-�� and IL-17 effector functions, as well as their regulation of neutrophils may dictate the outcome of non autoimmune-driven CNS inflammation, such as viral encephalitis.

During encephalomyelitis induced by the strain designated JHMV, CD4+ T cells not only contribute to antiviral effects by enhancing CD8+ T cell function within the CNS [29] but also mediate viral control in absence of CD8+ T cells [30]. Nevertheless, they also contribute to both clinical disease and demyelination [30]. To define the role of CD4+ relative to CD8+ T cells in viral encephalitis, memory CD4+ T cells from immunized donors were transferred into infected severe combined immunodeficiency (SCID) mice [31]. This study revealed an early morbidity and mortality in infected recipients of CD4+ T cells lacking the ability to secrete IFN-�� compared Dacomitinib to recipients of IFN-��-sufficient CD4+ T cells or infected unreconstituted control mice [31]. Notably, both memory populations were equally effective in controlling virus replication [31]. The lethal outcome was specific for CD4+ T cells lacking IFN-�� [31], but not for a similar memory CD8+ T cell population deficient in IFN-�� [32].