Vaccine-induced Aβ-specific CD8+ T cells do not trigger autoimmune neuroinflammation in a murine model of Alzheimer's disease

Background: active immunization against aβ was reported to have a therapeutic effect in murine models of alzheimer's disease. clinical aβ vaccination trial an1792 was interrupted due to the development in 6 % of the patients of meningoencephalitis likely involving pro-inflammatory cd4+ t cells. however,the potential implication of auto-aggressive anti-aβ cd8+ t cells has been poorly investigated. methods: potential mhc-i-restricted aβ-derived epitopes were first analyzed for their capacity to recruit functional cd8+ t cell responses in mouse models. their impact on migration of cd8+ t cells into the brain parenchyma and potential induction of meningoencephalitis and/or neuronal damage was investigated upon vaccination in the appps1 mouse model of ad. results: we identified one nonamer peptide,aβ33-41,which was naturally processed and presented in association with h-2-db molecule on neurons and cd11b+ microglia. upon optimization of anchor residues for enhanced binding to h-2-db,immunization with the modified aβ33-41np peptide elicited aβ-specific ifnγ-secreting cd8+ t cells,which are cytotoxic towards aβ-expressing targets. whereas t cell infiltration in the brain of appps1 mice is dominated by cd3+cd8- t cells and increases with disease evolution between 4 and 7 months of age,a predominance of cd3+cd8+ over cd3+cd8- cells was observed in 6- to 7-month-old appps1 but not in wt animals,only after vaccination with aβ33-41np. the number of cd11b+ mononuclear phagocytes,which significantly increases with age in the brain of appps1 mice,was reduced following immunization with aβ33-41np. despite peripheral activation of aβ-specific cd8+ cytotoxic effectors and enhanced infiltration of cd8+ t cells in the brain of aβ33-41np-immunized appps1 mice,no clinical signs of severe autoimmune neuroinflammation were observed. conclusions: altogether,these results suggest that aβ-specific cd8+ t cells are not major contributors to meningoencephalitis in response to aβ vaccination. © rosset et al.; licensee biomed central.