Background: Axonal damage is the main cause for permanent disability in patients with multiple sclerosis (MS), the most common chronic inflammatory CNS disorder in young adults. The majority of studies in the past focussed on the involvement of CD4+ T cells in MS pathogenesis both in humans as well as in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). Objective: Although several recent findings demonstrated the involvement of CD8+ T cells in MS and established a pathogenic role of myelln-specific CD8+ T cells in the animal model, mechanistic insights into CD8-driven CNS damage are lacking. Methods: To observe the interactions between antigen-specific T cells and their targets in living brain tissue, we applied a quasi-in vivo confocal imaging approach of organotypic brain slices derived from transgenic mice. In this setting, we used both CD8+ T cells (CTL) and CD4+ T cells carrying transgenic T cell receptors specific for the same antigen as effector cells. Results: While we could clearly demonstrate the capacity of CTLs to damage myelinated axons pulsed with cognate antigen, it remains unresolved to this date, whether axonal injury is the result of a targeted hit against the axon itself or the consequence of an attack against the myelin structure (collateral damage). To specifically answer this question, we next restricted the transgenic expression of the cognate antigen exclusively to the cytosol of oligodendrocytes. Conclusions: Here, we could unambigously show that axonal injury is the result of "collateral damage" by antigen-specific CTL targeting their cognate antigen presented by oligodendrocytes.