title: Vaccine-induced Aβ-specific CD8+ T cells do not trigger autoimmune neuroinflammation in a murine model of Alzheimer's disease.
abstract: 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.
authors.affiliation: INSERM, UMR_S 938, CdR Saint-Antoine, Laboratory Immune System, Neuroinflammation and Neurodegenerative Diseases, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, F-75012, Paris, France. martine.rosset@inserm.fr.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CdR Saint-Antoine, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, F-75012, Paris, France. martine.rosset@inserm.fr.
authors.forename: Martine Bruley
authors.initials: MB
authors.lastname: Rosset
authors.affiliation: INSERM, UMR_S 938, CdR Saint-Antoine, Laboratory Immune System, Neuroinflammation and Neurodegenerative Diseases, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, F-75012, Paris, France. luigaby@yahoo.fr.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CdR Saint-Antoine, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, F-75012, Paris, France. luigaby@yahoo.fr.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Lui
authors.affiliation: INSERM, UMR_S 938, CdR Saint-Antoine, Laboratory Immune System, Neuroinflammation and Neurodegenerative Diseases, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, F-75012, Paris, France. cira.dansokho@inserm.fr.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CdR Saint-Antoine, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, F-75012, Paris, France. cira.dansokho@inserm.fr.
authors.forename: Cira
authors.initials: C
authors.lastname: Dansokho
authors.affiliation: INSERM, UMR_S 938, CdR Saint-Antoine, Laboratory Immune System, Neuroinflammation and Neurodegenerative Diseases, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, F-75012, Paris, France. Thomas.chaigneau@inserm.fr.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CdR Saint-Antoine, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, F-75012, Paris, France. Thomas.chaigneau@inserm.fr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Chaigneau
authors.affiliation: INSERM, UMR_S 938, CdR Saint-Antoine, Laboratory Immune System, Neuroinflammation and Neurodegenerative Diseases, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, F-75012, Paris, France. guillaume.dorothee@inserm.fr.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CdR Saint-Antoine, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, F-75012, Paris, France. guillaume.dorothee@inserm.fr.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Dorothée
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology* / Q000473:pathology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015789:HLA-A2 Antigen / Q000235:genetics / Q000378:metabolism; D015798:HLA-DR1 Antigen / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016233:Immunotherapy, Active / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000276:immunology; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D015798:HLA-DR1 Antigen; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments; D053764:Presenilin-1