IL-2 Suppression of IL-12p70 by a Recombinant HSV-1 Expressing IL-2 Induces T-Cell Auto-Reactivity and CNS Demyelination

Abstract

To evaluate the role of cellular infiltrates in CNS demyelination in immunocompetent mice, we have used a model of multiple sclerosis (MS) in which different strains of mice are infected with a recombinant HSV-1 expressing IL-2. Histologic examination of the mice infected with HSV-IL-2 demonstrates that natural killer cells, dendritic cells, B cells, and CD25 (IL-2rα) do not play any role in the HSV-IL-2-induced demyelination. T cell depletion, T cell knockout and T cell adoptive transfer experiments suggest that both CD8+ and CD4+ T cells contribute to HSV-IL-2-induced CNS demyelination with CD8+ T cells being the primary inducers. In the adoptive transfer studies, all of the transferred T cells irrespective of their CD25 status at the time of transfer were positive for expression of FoxP3 and depletion of FoxP3 blocked CNS demyelination by HSV-IL-2. The expression levels of IL-12p35 relative to IL-12p40 differed in BM-derived macrophages infected with HSV-IL-2 from those infected with wild-type HSV-1. HSV-IL-2-induced demyelination was blocked by injecting HSV-IL-2-infected mice with IL-12p70 DNA. This study demonstrates that suppression of the IL-12p70 function of macrophages by IL-2 causes T cells to become auto-aggressive. Interruption of this immunoregulatory axis results in demyelination of the optic nerve, the spinal cord and the brain by autoreactive T cells in the HSV-IL-2 mouse model of MS.

Role of Interleukin-2 and Herpes Simplex Virus 1 in Central Nervous System Demyelination in Mice

“…1. Consistent with the results obtained when mice were infected with HSV-IL-2 (18)(19)(20)24), administration of murine IL-2 using an implanted miniature osmotic pump and ocular infection with wt HSV-1 induced demyelination in the ON, SC, and brain of all mice tested (Fig. 1A, rIL-2 protein ϩ HSV-1) but was not observed in mice treated with murine IL-2 in the absence of ocular infection (Fig.…”

“…Overall, the degree of demyelination in brain, spinal cord, and optic nerve of infected mice was similar following injection of mice with IL-2 protein, IL-2 DNA, or IL-2 peptides. Moreover, this demyelination was similar to that in HSV-IL-2-infected mice (17)(18)(19)(20).…”

“…We have shown that infection of different strains of mice with the HSV-IL-2 recombinant resulted in CNS demyelination (17,18). We have also found that infection of mice with a recombinant HSV-1 expressing IL-12p70 or injection of mice with IL-12p70 DNA blocks the CNS demyelination induced by the HSV-IL-2 recombinant (19,20).…”

“…Our published data establish that ocular infection of mice with HSV-IL-2 elicits demyelination of the optic nerve, spinal cord, and brain (18)(19)(20)24). In these studies, we looked at the time course of appearance of demyelination in mice infected with HSV-IL-2 (18)(19)(20)24).…”

“…In addition, the HSV-IL-2-infected mice developed optic neuropathy, as determined by changes in the visual evoked cortical potentials (VECPs) (18). Using knockout mice, depletion, and transfer studies, we found that both CD8 ϩ and CD4 ϩ T cells contributed to HSV-IL-2-induced central nervous system (CNS) demyelination, with CD8 ϩ T cells being the primary inducers (19). We have also found that infection of mice with a recombinant HSV-1 isolate expressing IL-12p70 or injection of mice with IL12p70 DNA blocks the CNS demyelination induced by HSV-IL-2 (19,20).…”