IL-12 and PGE 2 promote and inhibit, respectively, the development of Th1 responses. Production of these mediators by APC residing in the central nervous system (CNS) may be involved in the local regulation of the T cell phenotype during infectious and autoimmune CNS diseases. In the present study we have examined IL-12 and PGE 2 secretion by cultured microglia and astrocytes from the mouse brain upon Ag-dependent interaction with IA d-restricted, OVA 323–339 specific TCR transgenic Th1 and Th2 cell lines. We show that microglia, which restimulate efficiently both Th1 and Th2 cells, secrete IL-12 upon Ag-dependent interaction with Th1, but not with Th2 cells. Th1-driven IL-12 production depends on TCR ligation by MHC class II/peptide complexes, CD40 engagement on microglia, and IFN-γ secretion by activated Th1 cells. Th1 and, to a lesser extent, Th2 cells also stimulate the production of PGE 2 by microglia. T cell-mediated induction of PGE 2 requires MHC class II/peptide/TCR interactions but does not depend on CD40 engagement or on the presence of IFN-γ. Astrocytes, which preferentially activate Th2 cells, fail to produce IL-12 and secrete negligible amounts of PGE 2 upon interaction with either Th1 or Th2 cells. These results suggest that during CNS infection or immunopathology, IL-12 produced by microglia upon Ag-specific interaction with Th1 cells may further skew the immune response to Th1, whereas the T cell-dependent production of PGE 2 by microglia may represent a negative feedback mechanism, limiting the propagation of Th1 responses.