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

Background: Active immunization against A beta was reported to have a therapeutic effect in murine models of Alzheimer's disease. Clinical A beta 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-A beta CD8(+) T cells has been poorly investigated. Methods: Potential MHC-I-restricted A beta-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, A beta 33-41, 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 A beta 33-41NP peptide elicited A beta-specific IFN gamma-secreting CD8(+) T cells, which are cytotoxic towards A beta-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 A beta 33-41NP. The number of CD11b(+) mononuclear phagocytes, which significantly increases with age in the brain of APPPS1 mice, was reduced following immunization with A beta 33-41NP. Despite peripheral activation of A beta-specific CD8(+) cytotoxic effectors and enhanced infiltration of CD8(+) T cells in the brain of A beta 33-41NP-immunized APPPS1 mice, no clinical signs of severe autoimmune neuroinflammation were observed. Conclusions: Altogether, these results suggest that A beta-specific CD8(+) T cells are not major contributors to meningoencephalitis in response to A beta vaccination.