CD8+–Dependent CNS Demyelination Following Ocular Infection of Mice With a Recombinant HSV–1 Expressing Murine Il–2

Abstract

Abstract: : Purpose: We sought (1) to determine if, similar to multiple sclerosis (MS), a recombinant HSV–1 expressing IL–2 can cause optic neuritis (ON) in ocularly infected mice and (2) to identify which cellular infiltrates are involved in CNS demyelination.Methods: Female BALB/c and C57BL/6 mice were infected ocularly with HSV–IL–2, HSV–IL–4, HSV–IFN–γ, HSV–IL–2 + HSV–IL–4, or one of three control viruses. CNS demyelination of infected mice were monitored by Luxol Fast Blue staining while the presence of infiltrates in brains and optic nerves were measured by immunostaining and FACS analysis. Mice depleted of CD4⁺ or CD8⁺ T cells were examined for their ability to withstand CNS demyelination induced by HSV–IL–2. Results:Histological examination of mice infected with HSV–IL–2 demonstrated that demyelination lesions were found in optic nerves of infected mice at various times post infection, while mice infected with other recombinant viruses or control viruses did not exhibit such phenotypes. Flow cytometry and immunostaining revealed elevated levels of both CD4⁺ and CD8⁺ T cells and macrophages in HSV–IL–2 infected mice. However, T cell depletion studies suggest that only CD8⁺ T cells are directly involved in the demyelination process. Conclusions: Our results demonstrate for the first time that infection of mice with recombinant HSV–1 expressing IL–2, but not IFN–γ or IL–4 or control viruses, results in demyelination in the optic nerve as well as in the brain and the spinal cord, as determined histologically. In addition, the HSV–IL–2–induced CNS demyelination was associated with memory CD8⁺ T cells having a CD62L^hiCD45RB^lo phenotype.

Keywords: autoimmune disease • herpes simplex virus • immunomodulation/immunoregulation