title: MHC-independent genetic factors control the magnitude of CD4+ T cell responses to amyloid-β peptide in mice through regulatory T cell-mediated inhibition.
abstract: Accumulation of amyloid-β peptide (Aβ) is considered the triggering factor of pathogenic lesions in Alzheimer's disease (AD), and vaccines targeting Aβ are promising therapeutic options. However, the occurrence of meningoencephalitides attributed to T cell responses in 6% of Aβ-immunized patients underscores the need for a better understanding of T cell responses to Aβ. We characterized the parameters controlling the magnitude of Aβ-specific CD4(+) T cell responses in mice. T cell responsiveness to Aβ1-42 was highly heterogeneous between mouse strains of different H-2 haplotypes, with SJL/J (H-2(s)) mice displaying a strong response, mainly specific for Aβ10-24, and C57BL/6 (H-2(b)) mice displaying a weak response to Aβ16-30. Surprisingly, C57BL/6 mice congenic for the H-2(s) haplotype (B6.H-2(S)), which display a "permissive" MHC class II allele for presentation of the immunodominant Aβ10-24 epitope, showed a very weak CD4(+) T cell response to Aβ, suggesting that MHC-independent genes downmodulate Aβ-specific CD4(+) T cell responses in C57BL/6 background. Vaccine-induced CD4(+) T cell responses to Aβ were significantly enhanced in both C57BL/6 and B6.H-2(S) mice upon depletion of regulatory T cells (Tregs), whereas Treg-depleted SJL/J mice displayed unaltered Aβ-specific T cell responses. Finally, Treg depletion in C57BL/6 transgenic APPPS1 mice, a mouse model of AD, results in enhanced vaccine-induced CD4(+) T cell responses in AD compared with wild-type animals. We concluded that the magnitude of Aβ-specific CD4(+) T cell responses is critically controlled in both physiological and pathological settings by MHC-independent genetic factors that determine the overall potency of Aβ-specific Treg responses.
authors.affiliation: INSERM, Unité Mixte de Recherche S 938, Laboratoire Système Immunitaire et Maladies Conformationnelles, Hôpital Saint-Antoine, F-75012 Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Toly-Ndour
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Lui
authors.forename: Maria Manuel
authors.initials: MM
authors.lastname: Nunes
authors.forename: Martine
authors.initials: M
authors.lastname: Bruley-Rosset
authors.forename: Pierre
authors.initials: P
authors.lastname: Aucouturier
authors.forename: Guillaume
authors.initials: G
authors.lastname: Dorothée
mesh_terms: D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000008:administration & dosage* / Q000037:antagonists & inhibitors* / Q000276:immunology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006183:H-2 Antigens / Q000235:genetics* / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000008:administration & dosage; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000037:antagonists & inhibitors* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C489629:H-2A(b) antigen, mouse; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)