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Brain. 2016 Apr;139(Pt 4):1237-51. doi: 10.1093/brain/awv408. Epub 2016 Feb 1.

Regulatory T cells delay disease progression in Alzheimer-like pathology.

Author information

1
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.
2
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.
3
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.
4
4 Bioinformatics Platform, Faculty of Medicine Paris Descartes, Hôpital Necker-Enfants Malades, F-75015 Paris, France.
5
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.
6
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.

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.

KEYWORDS:

Alzheimer’s disease; immunotherapy; microglia; regulatory T cells

PMID:
26912648
DOI:
10.1093/brain/awv408
[Indexed for MEDLINE]

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