Microglia-Mediated Nitric Oxide Cytotoxicity of T Cells Following Amyloid β-Peptide Presentation to Th1 Cells
Abstract
Alzheimer's disease is marked by progressive accumulation of amyloid beta-peptide (Abeta) which appears to trigger neurotoxic and inflammatory cascades. Substantial activation of microglia as part of a local innate immune response is prominent at sites of Abeta plaques in the CNS. However, the role of activated microglia as Abeta APCs and the induction of adaptive immune responses has not been investigated. We have used primary microglial cultures to characterize Abeta-Ag presentation and interaction with Abeta-specific T cells. We found that IFN-gamma-treated microglia serve as efficient Abeta APCs of both Abeta1-40 and Abeta1-42, mediating CD86-dependent proliferation of Abeta-reactive T cells. When cultured with Th1 and Th2 subsets of Abeta-reactive T cells, Th1, but not Th2, cells, underwent apoptosis after stimulation, which was accompanied by increased levels of IFN-gamma, NO, and caspase-3. T cell apoptosis was prevented in the presence of an inducible NO synthase type 2 inhibitor. Microglia-mediated proliferation of Abeta-reactive Th2 cells was associated with expression of the Th2 cytokines IL-4 and IL-10, which counterbalanced the toxic levels of NO induced by Abeta. Our results demonstrate NO-dependent apoptosis of T cells by Abeta-stimulated microglia which may enhance CNS innate immune responses and neurotoxicity in Alzheimer's disease. Secretion of NO by stimulated microglia may underlie a more general pathway of T cell death in the CNS seen in neurodegenerative…
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T cells can influence microglial differentiation.
“In vitro data showed a ‘cross-talking’ between microglia and T cells, microglia can serve as antigen-presenting cells for Aβ-reactive T cells and, in turn, T cells themselves can influence microglial differentiation [161–163].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [161]
Microglia can serve as antigen-presenting cells for Aβ-reactive T cells.
“In vitro data showed a ‘cross-talking’ between microglia and T cells, microglia can serve as antigen-presenting cells for Aβ-reactive T cells and, in turn, T cells themselves can influence microglial differentiation [161–163].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [161]
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- Authors
- Monsonego, A., Imitola, J., Zota, V., Oida, T., & Weiner, H. L.
- Affiliations
- Brigham and Women's Hospital (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2003-09-01
- Volume
- 171
- Issue
- 5
- Pages
- 2216-2224
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2135331060
- Cited by
- 91
- References
- 5
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 8 · 2019: 2 · 2017: 2 · 2016: 5 · 2015: 2 · 2014: 1 · 2013: 3 · 2012: 3
- FWCI
- 5.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01 AI 435801)
- National Institute of Neurological Disorders and Stroke (NS 38037-01A1, P01NS038037)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- microglia, nitric oxide, T cell apoptosis, amyloid-beta, Th1 cells, Th2 cells, antigen presentation, Alzheimer's disease, interferon-gamma, inducible nitric oxide synthase, CD86, IL-4, IL-10, neuroinflammation, neurodegeneration, adaptive immune response
- MeSH terms
- Animals, Cell Division, Cell Line, Cells, Cultured, Humans, Interferon-gamma, Lymphocyte Activation, Membrane Glycoproteins, Mice, Inbred C57BL, Nitric Oxide, Antigens, CD, T-Lymphocyte Subsets, Amyloid beta-Peptides, Apoptosis, Microglia, Antigen Presentation, Th1 Cells, Th2 Cells, CD11b Antigen, Mice, B7-2 Antigen
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