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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-D b  molecule on neurons and CD11b +  microglia. Upon optimization of anchor residues for enhanced binding to H-2-D b , 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.

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