Microglia-mediated nitric oxide cytotoxicity of T cells following amyloid β-peptide presentation to Th1 cells

Alon Monsonego, Jaime Imitola, Victor Zota, Takatoku Oida, Howard L. Weiner

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

Alzheimer's disease is marked by progressive accumulation of amyloid β-peptide (Aβ) 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 Aβ plaques in the CNS. However, the role of activated microglia as Aβ APCs and the induction of adaptive immune responses has not been investigated. We have used primary microglial cultures to characterize Aβ-Ag presentation and interaction with Aβ-specific T cells. We found that IFN-γ-treated microglia serve as efficient Aβ APCs of both Aβ1-40 and Aβ1-42, mediating CD86-dependent proliferation of Aβ-reactive T cells. When cultured with Th1 and Th2 subsets of Aβ-reactive T cells, Th1, but not Th2, cells, underwent apoptosis after stimulation, which was accompanied by increased levels of IFN-γ, NO, and caspase-3. T cell apoptosis was prevented in the presence of an inducible NO synthase type 2 inhibitor. Microglia-mediated proliferation of Aβ-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 Aβ. Our results demonstrate NO-dependent apoptosis of T cells by Aβ-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 diseases. Furthermore, Th2 type T cell responses may have a beneficial effect on this process by down-regulation of NO and the proinflammatory environment.

Original languageEnglish
Pages (from-to)2216-2224
Number of pages9
JournalJournal of Immunology
Volume171
Issue number5
DOIs
StatePublished - 1 Sep 2003
Externally publishedYes

Fingerprint

Dive into the research topics of 'Microglia-mediated nitric oxide cytotoxicity of T cells following amyloid β-peptide presentation to Th1 cells'. Together they form a unique fingerprint.

Cite this