IFN-γ protects from lethal IL-17 mediated viral encephalomyelitis independent of neutrophils

Background: the interplay between ifn-γ,il-17 and neutrophils during cns inflammatory disease is complex due to cross-regulatory factors affecting both positive and negative feedback loops. these interactions have hindered the ability to distinguish the relative contributions of neutrophils,th1 and th17 cell-derived effector molecules from secondary mediators to tissue damage and morbidity.methods: encephalitis induced by a gliatropic murine coronavirus was used as a model to assess the direct contributions of neutrophils,ifn-γ and il-17 to virus-induced mortality. cns inflammatory conditions were selectively manipulated by adoptive transfer of virus-primed wild-type (wt) or ifn-γ deficient (gko) memory cd4+ t cells into infected scid mice,coupled with antibody-mediated neutrophil depletion and cytokine blockade.results: transfer of gko memory cd4+ t cells into infected scid mice induced rapid mortality compared to recipients of wt memory cd4+ t cells,despite similar virus control and demyelination. in contrast to recipients of wt cd4+ t cells,extensive neutrophil infiltration and il-17 expression within the cns in recipients of gko cd4+ t cells provided a model to directly assess their contribution(s) to disease. recipients of wt cd4+ t cells depleted of ifn-γ did not express il-17 and were spared from mortality despite abundant cns neutrophil infiltration,indicating that mortality was not mediated by excessive cns neutrophil accumulation. by contrast,il-17 depletion rescued recipients of gko cd4+ t cells from rapid mortality without diminishing neutrophils or reducing gm-csf,associated with pathogenic th17 cells in cns autoimmune models. furthermore,co-transfer of wt and gko cd4+ t cells prolonged survival in an ifn-γ dependent manner,although il-17 transcription was not reduced.conclusions: these data demonstrate that il-17 mediates detrimental clinical consequences in an ifn-γ-deprived environment,independent of extensive neutrophil accumulation or gm-csf upregulation. the results also suggest that ifn-γ overrides the detrimental il-17 effector responses via a mechanism downstream of transcriptional regulation. © 2012 savarin et al.; licensee biomed central ltd.