A fundamental question in neuroimmunology is the extent to which CD8 T cells actively engage virusinfected neurons. In the Theiler's murine encephalomyelitis virus (TMEV) model of multiple sclerosis, an effective central nervous system (CNS)-infiltrating antiviral CD8 T cell response offers protection from this demyelinating disease. However , the specific CNS cell types engaged by these protective CD8 T cells in TMEV-resistant strains remains unknown. We used confocal microscopy to visualize

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... e morphology, migration , and specific cellular interactions between adoptively transferred CD8 T cells and specific CNS cell types. Adoptively transferred GFP؉ CD8؉ splenocytes migrated to the brain and became 93% specific for the immunodominant virus epitope D b :VP2 121-130 . These CD8 T cells also polarized T cell receptor, CD8 protein , and granzyme B toward target neurons. Furthermore , we observed CD8 T cells forming cytoplasmic processes up to 45 m in length. Using live tissue imaging, we determined that these T cell-extended processes (TCEPs) could be rapidly formed and were associated with migratory behavior through CNS tissues. These studies provide evidence that antiviral CD8 T cells have the capacity to engage virus-infected neurons in vivo and are the first to document and measure the rapid formation of TCEPs on these brain-infiltrating lymphocytes using live tissue imaging. Supplemental material for this article can be found on http://ajp. amjpathol.org. Current address of I.P., Department of Neurology, Mayo Clinic, Rochester MN. Address reprint requests to Aaron J. Johnson,