Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss

Abstract

Neurons are postmitotic and thus irreplaceable cells of the central nervous system (CNS). Accordingly, CNS inflammation with resulting neuronal damage can have devastating consequences. We investigated molecular mediators and structural consequences of CD8(+) T lymphocyte (CTL) attack on neurons in vivo. In a viral encephalitis model in mice, disease depended on CTL-derived interferon-(IFN-) and neuronal IFN-signaling. Downstream STAT1 phosphorylation and nuclear translocation in neurons were associated with dendrite and synapse loss (deafferentation). Analogous molecular and structural alterations were also found in human Rasmussen encephalitis, a CTL-mediated human autoimmune disorder of the CNS. Importantly, therapeutic intervention by IFN-blocking antibody prevented neuronal deafferentation and clinical disease without reducing CTL responses or CNS infiltration. These findings identify neuronal IFN-signaling as a novel target for neuroprotective interventions in CTLmediated CNS disease.

Interferon gamma in autoimmunity: A complicated player on a complex stage

“…However other studies have demonstrated a pathogenic impact of IFNc in demyelinating disease [134,135], while still others saw no effect of IFNc deficiency on demyelination associated with an infection [136]. Further, there are clear indications that IFNc can exacerbate neuroinflammatory disease and drive neuronal loss in other settings [137].…”

Toxoplasmainduces stripping of perisomatic inhibitory synapses

“…It was hypothesized that these microglia played an active role in the removal of these synapses, a process termed synaptic stripping. Synaptic stripping has been observed not only after axotomy or injury, but also following infection or inflammation (Di Liberto et al 2018;Kreutzfeldt et al 2013;Trapp et al 2007;Chen et al 2014), and it involves not only excitatory perisomatic synapses (like those on lower motoneurons; Blinzinger and Kreutzberg 1968) but also inhibitory perisomatic synapses (like those in neocortex and hippocampus; Di Liberto et al 2018;Chen et al 2014). While activation of microglia following insult and inflammation may lead to synaptic stripping, it does not in all cases (Siskova et al 2009;Perry and O'Conner 2010), nor is activation a requirement for microglial to phagocytose synaptic elements.…”

Immune Surveillance of the CNS following Infection and Injury

“…During LCMV meningitis, CD8 + T cells can induce a pathogenic recruitment of innate myelomonocytic cells that break down cerebral blood vessels and contribute to fatal CNS edema (Figure 1, Movie 2) [54]. CD8 + T cells can also release IFN-γ onto virally infected neurons, promoting loss of dendrites and synapses [55]. In contrast, another recent study showed that cerebral pathology does not always result from antiviral T cell activity in the infected CNS.…”