Transgenic expression of H-2Db class I molecules influences the development of brain atrophy during Picornavirus infection

Abstract

Abstract Brain atrophy is a common feature of numerous neurological diseases in which the role of neuroinflammation remains poorly defined. We have previously demonstrated the development of brain and spinal cord atrophy in the Theiler’s murine encephalomyelitis virus (TMEV) model of multiple sclerosis. However, cellular and molecular mechanisms of brain atrophy remain poorly understood. We therefore evaluated the contribution of major histocompatibility (MHC) class I molecules in atrophy development during TMEV infection. To accomplish this, we created a novel transgenic FVB/NJ mouse by introducing the H-2Db (Db) class I molecule. Expression of Db class I molecule confers resistance to persistent TMEV infection and demyelination in the normally susceptible FVB/NJ strain (H2-Dq class I haplotype). Next, we compared the development of brain atrophy, assessed by volumetric analysis of T2-weighted MRIs, in FVB/Db mice to wild-type FVB/NJ mice following viral infection. FVB/NJ mice did not significant brain develop atrophy over 4 months, whereas significant brain atrophy was observed in the FVB/Db mice. FVB/Db mice also developed a significant increase in the overall number of CNS infiltrating CD8 T cells and a strong CD8 T cell response towards an immunodominant Db TMEV epitope, VP2121-130. A number of CD8 T cells were also observed in close proximity to virus infected neurons. We therefore propose a hypothesis that class I restricted CD8 T cell responses promote the development of brain atrophy. This model provides a unique opportunity to analyze the contribution of immune cells to neuronal loss and brain atrophy in a system where persistent virus infection and demyelination are not confounding variables.