Glucocorticoids (GC) are essential neuroendocrine regulators of the immune system during stress, and prolonged psychological stress has been shown to be immunosuppressive. However, little is known about how GC influence the role of microglia, the most potent antigen presenting cell (APC) residing in the central nervous system (CNS), in the T cell immune response during stress. Therefore, we investigated whether GC could modulate the function of microglia and thus affect T cell response in vitro. In interferon (IFN)-gamma-stimulated microglia, GC reduced secretion of the pro-inflammatory cytokines interleukin (IL)-12, IL-6 and tumor necrosis factor (TNF)-alpha, inhibited expression of major histocompatibility complex (MHC) class II, and costimulators CD40 and CD80 on microglia, but up-regulated the expression of co-inhibitors B7-H1 and B7-DC. In addition, GC induced the apoptosis of microglia directly. As a result, treatment of microglia with GC reduced their ability to stimulate CD4(+) Th cell proliferation primed by anti-CD3 monoclonal antibody (mAb), and induced a shift to the Th2 response with the imbalance between Th1 and Th2 cytokines. Our data suggest that the inhibitory effects of GC on the APC function of microglia may contribute to the stress-induced suppression of T cell response in the CNS.