title: Regulatory T cells delay disease progression in Alzheimer-like pathology.
abstract: Recent studies highlight the implication of innate and adaptive immunity in the pathophysiology of Alzheimer's disease, and foster immunotherapy as a promising strategy for its treatment. Vaccines targeting amyloid-β peptide provided encouraging results in mouse models, but severe side effects attributed to T cell responses in the first clinical trial AN1792 underlined the need for better understanding adaptive immunity in Alzheimer's disease. We previously showed that regulatory T cells critically control amyloid-β-specific CD4(+) T cell responses in both physiological and pathological settings. Here, we analysed the impact of regulatory T cells on spontaneous disease progression in a murine model of Alzheimer's disease. Early transient depletion of regulatory T cells accelerated the onset of cognitive deficits in APPPS1 mice, without altering amyloid-β deposition. Earlier cognitive impairment correlated with reduced recruitment of microglia towards amyloid deposits and altered disease-related gene expression profile. Conversely, amplification of regulatory T cells through peripheral low-dose IL-2 treatment increased numbers of plaque-associated microglia, and restored cognitive functions in APPPS1 mice. These data suggest that regulatory T cells play a beneficial role in the pathophysiology of Alzheimer's disease, by slowing disease progression and modulating microglial response to amyloid-β deposition. Our study highlights the therapeutic potential of repurposed IL-2 for innovative immunotherapy based on modulation of regulatory T cells in Alzheimer's disease.
authors.affiliation: 1 INSERM, UMRS 938, CdR Saint-Antoine, Laboratory Immune System, Neuroinflammation and Neurodegenerative Diseases, Hôpital St-Antoine, F-75012, Paris, France 2 Sorbonne Universités, UPMC Univ Paris 06, UMRS 938, CdR Saint-Antoine, Hôpital Saint-Antoine, F-75012, Paris, France guillaume.dorothee@inserm.fr.
authors.forename: Cira
authors.initials: C
authors.lastname: Dansokho
authors.affiliation: 1 INSERM, UMRS 938, CdR Saint-Antoine, Laboratory Immune System, Neuroinflammation and Neurodegenerative Diseases, Hôpital St-Antoine, F-75012, Paris, France 2 Sorbonne Universités, UPMC Univ Paris 06, UMRS 938, CdR Saint-Antoine, Hôpital Saint-Antoine, F-75012, Paris, France guillaume.dorothee@inserm.fr.
authors.forename: Dylla
authors.initials: D
authors.lastname: Ait Ahmed
authors.affiliation: 2 Sorbonne Universités, UPMC Univ Paris 06, UMRS 938, CdR Saint-Antoine, Hôpital Saint-Antoine, F-75012, Paris, France 3 INSERM, UMRS 938, CdR Saint-Antoine, Laboratory Neuroendocrine mechanisms of longevity and age-related diseases, Hôpital St-Antoine, F-75012, Paris, France guillaume.dorothee@inserm.fr.
authors.forename: Saba
authors.initials: S
authors.lastname: Aid
authors.affiliation: 1 INSERM, UMRS 938, CdR Saint-Antoine, Laboratory Immune System, Neuroinflammation and Neurodegenerative Diseases, Hôpital St-Antoine, F-75012, Paris, France 2 Sorbonne Universités, UPMC Univ Paris 06, UMRS 938, CdR Saint-Antoine, Hôpital Saint-Antoine, F-75012, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Toly-Ndour
authors.affiliation: 1 INSERM, UMRS 938, CdR Saint-Antoine, Laboratory Immune System, Neuroinflammation and Neurodegenerative Diseases, Hôpital St-Antoine, F-75012, Paris, France 2 Sorbonne Universités, UPMC Univ Paris 06, UMRS 938, CdR Saint-Antoine, Hôpital Saint-Antoine, F-75012, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Chaigneau
authors.affiliation: 1 INSERM, UMRS 938, CdR Saint-Antoine, Laboratory Immune System, Neuroinflammation and Neurodegenerative Diseases, Hôpital St-Antoine, F-75012, Paris, France 2 Sorbonne Universités, UPMC Univ Paris 06, UMRS 938, CdR Saint-Antoine, Hôpital Saint-Antoine, F-75012, Paris, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Calle
authors.affiliation: 4 Bioinformatics Platform, Faculty of Medicine Paris Descartes, Hôpital Necker-Enfants Malades, F-75015 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cagnard
authors.affiliation: 2 Sorbonne Universités, UPMC Univ Paris 06, UMRS 938, CdR Saint-Antoine, Hôpital Saint-Antoine, F-75012, Paris, France 3 INSERM, UMRS 938, CdR Saint-Antoine, Laboratory Neuroendocrine mechanisms of longevity and age-related diseases, Hôpital St-Antoine, F-75012, Paris, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Holzenberger
authors.affiliation: 5 INSERM, U932, Institut Curie, Section Recherche; Center of Clinical Investigation (CIC-BT-507), F-75005, Paris, France 6 Sorbonne Universités, UPMC Univ Paris 06, CNRS, UMR7211, Immunology-Immunopathology-Immunotherapy, F-75013 Paris, France.
authors.forename: Eliane
authors.initials: E
authors.lastname: Piaggio
authors.affiliation: 1 INSERM, UMRS 938, CdR Saint-Antoine, Laboratory Immune System, Neuroinflammation and Neurodegenerative Diseases, Hôpital St-Antoine, F-75012, Paris, France 2 Sorbonne Universités, UPMC Univ Paris 06, UMRS 938, CdR Saint-Antoine, Hôpital Saint-Antoine, F-75012, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Aucouturier
authors.affiliation: 1 INSERM, UMRS 938, CdR Saint-Antoine, Laboratory Immune System, Neuroinflammation and Neurodegenerative Diseases, Hôpital St-Antoine, F-75012, Paris, France 2 Sorbonne Universités, UPMC Univ Paris 06, UMRS 938, CdR Saint-Antoine, Hôpital Saint-Antoine, F-75012, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Dorothée
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D016564:Amyloid beta-Protein Precursor; D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology; D018450:Disease Progression; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053764:Presenilin-1; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000502:physiology*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D007376:Interleukin-2; C508853:PSEN1 protein, human; D053764:Presenilin-1
keywords: Alzheimer’s disease; immunotherapy; microglia; regulatory T cells