Activation of mixed glia by A-beta-specific Th1 and Th17 cells and its regulation by Th2 cells

Abstract

Microglia are innate immune cells of the CNS, that act as antigen-presenting cells (APC) for antigen-specific T cells and respond to inflammatory stimuli, such as amyloid-beta (A?), resulting in the release of neurotoxic factors and pro-inflammatory cytokines. Astrocytes can also act as APC and modulate the function of microglia. However, the role of distinct T cell subtypes, in particular Th17 cells, in glial activation and subsequent modulatory effects of Th2 cells are poorly understood. Here, we generated A?-specific Th1, Th2, and Th17 cells and examined their role in modulating A?-induced activation of microglia in a mixed glial culture, a preparation which mimics the complex APC types in the brain. We demonstrated that mixed glia acted as an effective APC for A?-specific Th1 and Th17 cells. Addition of A?-specific Th2 cells suppressed the A?-induced IFN-? production by Th1 cells and IL-17 production by Th17 cells with glia as the APC. Co-culture of A?-specific Th1 or Th17 cells with glia markedly enhanced A?-induced pro-inflammatory cytokine production and expression of MHC class II and co-stimulatory molecules on the microglia. Addition of A?-specific Th2 cells inhibited Th17 cell-induced IL-1? and IL-6 production by mixed glia and attenuated Th1 cell-induced CD86 and CD40 expression on microglia. The modest enhancement of MHC class II and CD86 expression on astrocytes by A?-specific Th1 and Th17 was not attenuated by Th2 cells. These data indicate that A?-specific Th1 and Th17 cells induce inflammatory activation of glia, and that this is in part regulated by Th2 cells.