CD4+ effector T cells accelerate Alzheimer's disease in mice.
Alzheimer Disease
/ pathology
Amyloid beta-Protein Precursor
/ genetics
Amyloidosis
/ pathology
Animals
CD4-Positive T-Lymphocytes
/ pathology
Cognition Disorders
/ pathology
Inflammation
/ genetics
Mice
Mice, Transgenic
Presenilin-1
/ genetics
T-Lymphocytes, Regulatory
/ immunology
Th1 Cells
/ immunology
Th17 Cells
/ immunology
APP/PS1 transgenic mice
Alzheimer’s disease (AD)
Amyloid beta (Aβ)
Effector T cell (Teff)
Regulatory T cell (Treg)
T cell
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
19 Nov 2021
19 Nov 2021
Historique:
received:
02
07
2021
accepted:
28
10
2021
entrez:
20
11
2021
pubmed:
21
11
2021
medline:
1
3
2022
Statut:
epublish
Résumé
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as a key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered that begin early and persist throughout the disease. How these occur and whether they can be harnessed to halt disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teffs) that drive pro-inflammatory and neurodestructive immunity leading to cognitive impairments. Here, we investigated the role of effector immunity and how it could affect cellular-level disease pathobiology in an AD animal model. In this report, we developed and characterized cloned lines of amyloid beta (Aβ) reactive type 1 T helper (Th1) and type 17 Th (Th17) cells to study their role in AD pathogenesis. The cellular phenotype and antigen-specificity of Aβ-specific Th1 and Th17 clones were confirmed using flow cytometry, immunoblot staining and Aβ T cell epitope loaded haplotype-matched major histocompatibility complex II IA The propagated Aβ-Th1 and Aβ-Th17 clones were confirmed stable and long-lived. Treatment of APP/PS1 mice with Aβ reactive Teffs accelerated memory impairment and systemic inflammation, increased amyloid burden, elevated microglia activation, and exacerbated neuroinflammation. Both Th1 and Th17 Aβ-reactive Teffs progressed AD pathology by downregulating anti-inflammatory and immunosuppressive regulatory T cells (Tregs) as recorded in the periphery and within the central nervous system. These results underscore an important pathological role for CD4+ Teffs in AD progression. We posit that aberrant disease-associated effector T cell immune responses can be controlled. One solution is by Aβ reactive Tregs.
Sections du résumé
BACKGROUND
BACKGROUND
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as a key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered that begin early and persist throughout the disease. How these occur and whether they can be harnessed to halt disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teffs) that drive pro-inflammatory and neurodestructive immunity leading to cognitive impairments. Here, we investigated the role of effector immunity and how it could affect cellular-level disease pathobiology in an AD animal model.
METHODS
METHODS
In this report, we developed and characterized cloned lines of amyloid beta (Aβ) reactive type 1 T helper (Th1) and type 17 Th (Th17) cells to study their role in AD pathogenesis. The cellular phenotype and antigen-specificity of Aβ-specific Th1 and Th17 clones were confirmed using flow cytometry, immunoblot staining and Aβ T cell epitope loaded haplotype-matched major histocompatibility complex II IA
RESULTS
RESULTS
The propagated Aβ-Th1 and Aβ-Th17 clones were confirmed stable and long-lived. Treatment of APP/PS1 mice with Aβ reactive Teffs accelerated memory impairment and systemic inflammation, increased amyloid burden, elevated microglia activation, and exacerbated neuroinflammation. Both Th1 and Th17 Aβ-reactive Teffs progressed AD pathology by downregulating anti-inflammatory and immunosuppressive regulatory T cells (Tregs) as recorded in the periphery and within the central nervous system.
CONCLUSIONS
CONCLUSIONS
These results underscore an important pathological role for CD4+ Teffs in AD progression. We posit that aberrant disease-associated effector T cell immune responses can be controlled. One solution is by Aβ reactive Tregs.
Identifiants
pubmed: 34798897
doi: 10.1186/s12974-021-02308-7
pii: 10.1186/s12974-021-02308-7
pmc: PMC8603581
doi:
Substances chimiques
APP protein, human
0
Amyloid beta-Protein Precursor
0
PSEN1 protein, human
0
Presenilin-1
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
272Subventions
Organisme : NINDS NIH HHS
ID : R01 NS036126
Pays : United States
Organisme : NINDS NIH HHS
ID : P01 NS43985
Pays : United States
Organisme : NINDS NIH HHS
ID : P01 NS043985
Pays : United States
Organisme : NIDA NIH HHS
ID : P01 DA028555
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH121402
Pays : United States
Organisme : NIMH NIH HHS
ID : P01 MH064570
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG043540
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS034239
Pays : United States
Organisme : NINDS NIH HHS
ID : P01 NS31492
Pays : United States
Organisme : NIMH NIH HHS
ID : P30 MH062261
Pays : United States
Organisme : NINDS NIH HHS
ID : 2R01 NS034239
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS36126
Pays : United States
Organisme : NIMH NIH HHS
ID : P01 MH64570
Pays : United States
Organisme : NINDS NIH HHS
ID : P01 NS031492
Pays : United States
Informations de copyright
© 2021. The Author(s).
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