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

Background: The interplay between IFN-gamma, 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-gamma and IL-17 to virus-induced mortality. CNS inflammatory conditions were selectively manipulated by adoptive transfer of virus-primed wild-type (WT) or IFN-gamma 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-gamma 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-gamma dependent manner, although IL-17 transcription was not reduced. Conclusions: These data demonstrate that IL-17 mediates detrimental clinical consequences in an IFN-gamma-deprived environment, independent of extensive neutrophil accumulation or GM-CSF upregulation. The results also suggest that IFN-gamma overrides the detrimental IL-17 effector responses via a mechanism downstream of transcriptional regulation.