Context matters: Conflicting roles of interferon-γ signaling in CNS diseases

Interferon-gamma (IFNγ) is a pleiotropic cytokine produced by CD8+ and CD4+ Th1 T cells, natural killer cells, natural killer-T cells, and type 1 innate lymphoid cells. Canonical IFNγ-induced genes include cytokines, chemokines, antigen processing and presentation machinery, and other transcription factors that initiate secondary, cell type-specific IFNγ responses. Originally described as an antiviral molecule, additional roles for IFNγ in development, anti-infection immunity, and neurodegeneration have been described. However, IFNγ's downstream effects are highly context-dependent. Recent studies have uncovered extensive neuroimmune interactions within the CNS and implicated IFNγ in numerous CNS diseases, although these studies have produced conflicting results. This highlights a need for functional studies accounting for the spatial, temporal, and cellular complexities of CNS IFNγ signaling. Here, we summarize the current understanding of IFNγ signaling in CNS infections, multiple sclerosis/experimental autoimmune encephalomyelitis, and aging-associated neurodegenerative diseases and propose a framework for the design of future studies investigating the role of CNS IFNγ signaling.