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-Peptide Presentation to Th1 Cells 1
Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
Alzheimer’s disease is marked by progressive accumulation of amyloid 
-peptide (A) 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 A plaques in the CNS. However, the role of activated microglia as A APCs and the induction of adaptive immune responses has not been investigated. We have used primary microglial cultures to characterize A-Ag presentation and interaction with A-specific T cells. We found that IFN-
-treated microglia serve as efficient A APCs of both A1–40 and A1–42, mediating CD86-dependent proliferation of A-reactive T cells. When cultured with Th1 and Th2 subsets of A-reactive T cells, Th1, but not Th2, cells, underwent apoptosis after stimulation, which was accompanied by increased levels of IFN-, NO, and caspase-3. T cell apoptosis was prevented in the presence of an inducible NO synthase type 2 inhibitor. Microglia-mediated proliferation of A-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 A. Our results demonstrate NO-dependent apoptosis of T cells by A-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.
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