Virus antigen-specific CD8 T cells contribute to brain atrophy during Theiler’s murine encephalomyelitis virus (TMEV) infection of the CNS.

Abstract

Abstract Brain atrophy is a central feature of numerous neurological diseases for which the contribution of immune cells remains poorly defined. For example, in human multiple sclerosis, clonally expanded CD8 T cells have been observed in proximity to lesions, but their role in mediating brain atrophy has yet to be elucidated. This study aims to define how antigen-specific CD8 T cells contribute to brain atrophy in the TMEV model of neuroinflammation. Specific MHC class I haplotypes have been shown to dictate neuropathology and functional outcomes in mice following intracranial infection with TMEV. In this study, we demonstrate that transgenic FVB mice which express the H-2Db class I molecule rapidly clear picornavirus infection but at the cost of a novel neurodegenerative phenotype consistent with brain atrophy. Following TMEV infection out to four months, FVB mice expressing the Db class I molecule display increased lateral ventricular volume via T2-weighted MRI and hippocampal neuron loss by hematoxylin and eosin staining. Furthermore, these transgenic FVB mice present enhanced brain infiltration of virus-specific CD8 T cells for the immunodominant Db:VP2121–130 epitope. To address these findings mechanistically, we inhibited the Db:VP2121–130 epitope-specific CD8 T cell response and monitored the effect on brain atrophy. This inhibition strategy resulted in a reduction in brain atrophy to levels comparable to wild-type FVB controls. Not confounded by persistent infection or demyelination, these studies are the first to demonstrate antigen-specific CD8 T cells have the capacity to induce brain atrophy in a murine model of neurodegeneration.