Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice

We have established two mouse models of central nervous system (cns) demyelination that differ from most other available models of multiple sclerosis (ms) in that they represent a mixture of viral and immune triggers. in the first model,ocular infection of different strains of mice with a recombinant hsv-1 that expresses murine il-2 constitutively (hsv-il-2) causes cns demyelination. in the second model,depletion of macrophages causes cns demyelination in mice that are ocularly infected with wild-type (wt) hsv-1. in the present study,we found that the demyelination in macrophage-intact mice infected with hsv-il-2 was blocked by depletion of foxp3-expressing cells,while concurrent depletion of macrophages restored demyelination. in contrast,demyelination was blocked in the macrophage-depleted mice infected with wild-type hsv-1 following depletion of foxp3-expressing cells. in macrophage-depleted hsv-il-2-infected mice,demyelination was associated with the activity of both cd4+and cd8+t cells,whereas in macrophage-depleted mice infected with wt hsv-1,demyelination was associated with cd4+t cells. macrophage depletion or infection with hsv-il-2 caused an imbalance of t cells and th1 responses as well as alterations in il-12p35 and il-12p40 but not other members of the il-12 family or their receptors. demyelination was blocked by adoptive transfer of macrophages that were infected with hsv-il-12p70 or hsv-il-12p40 but not by hsv-il-12p35. these results indicate that suppression of il-12p70 formation by il-2 or following macrophage depletion causes t-cell autoreactivity leading to cns demyelination in hsv-1-infected mice. © 2017 lee et al.