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

Journal of Neuroinflammation

Guillaume Dorothée¹  Thomas Chaigneau¹  Cira Dansokho¹  Gabrielle Lui¹  Martine Bruley Rosset¹ 

[1] Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CdR Saint-Antoine, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, Paris, F-75012, France

关键词: Encephalitis;    CD8+ T cells;    Aβ peptide;    Vaccination;    Alzheimer’s disease;   

Others  :  1221991
DOI  :  10.1186/s12974-015-0317-5

 received in 2014-11-04, accepted in 2015-05-03,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Rosset et al.; licensee BioMed Central.

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